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Breast: Ductal carcinoma

Written2012-10Cathy B Moelans, Paul J van Diest
Department of Pathology, University Medical Center Utrecht, Utrecht, Heidelberglaan 100, PO Box 85500, 3508 GA, Utrecht, The Netherlands

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Identity

ICD-Topo C500-C506,C508-C509 BREAST
ICD-Morpho 8500/3 Infiltrating duct carcinoma, NOS
Atlas_Id 5593
Phylum Female organs: Breast::Ductal carcinoma
Other namesInfiltrating/invasive ductal carcinoma (IDC)
Carcinoma of no special type (NST) or not otherwise specified (NOS)

Classification

Note IDC represents 65 to 85 percent of all breast cancers. IDC originates in the transition between the breast's milk ducts and lobuli and invades surrounding breast tissue.
Note Figure 1. Main breast cancer histological types. From top left to bottom right: ductal NST, medullary, tubular, cribriform, mucinous and (squamous) metaplastic breast cancer.
    Invasive ductal carcinoma is a heterogeneous group with many different subtypes, some of them extremely rare. Each of these variants is associated with another pathological presentation and with a different prognosis compared to invasive ductal carcinoma of no special type (NST). As shown in Figure 1, some of the most important subclassifications are:
- Medullary carcinoma: younger age, association with BRCA1 mutation, 1-5% of breast carcinomas, rarely lymph node metastases, bad prognosis
- Metaplastic carcinoma: <1% of breast carcinomas, association with BRCA1 mutation, bad prognosis
- Mucinous/colloid carcinoma: older age, 1-6% of breast carcinomas, better prognosis
- Inverted papillary carcinoma: 1% of all breast carcinomas, better prognosis, striking lymphovascular invasion
- Tubular carcinoma: younger age, about 5% of breast carcinomas, excellent prognosis
- Cribriform carcinoma: younger age, good prognosis.

Clinics and Pathology

Disease Carcinoma of the breast is more common in the left breast than in the right, in a ratio of 110/100. Approximately 50% arise in the upper outer quadrant, 10% in each of the remaining quadrants, and 20% in the central or subareolar region. While the overwhelming majority of breast cancer cases in humans are women, men can also develop breast cancer.
Progression: One of the earliest detectable changes is loss of normal regulation of cell growth and polarity, resulting in early morphological changes such as atypical ductal hyperplasia (ADH) and columnar cell lesions (CCL). Next, genomic instability results in the formation of ductal carcinoma in situ (DCIS) lesions. In the most popular model to explain the development of IDC, low-grade DCIS lesions tend to progress to low-grade IDC, and high-grade DCIS tends to progress to high-grade IDC by accumulation of fairly specific chromosomal and gene alterations (Buerger et al., 2000; Hwang et al., 2004). The majority of molecular changes that are observed in breast cancer seem to be already evident in the DCIS stage (Mommers et al., 2001). Also, epigenetic changes such as methylation and microRNAs are believed to play role in the disease progression and occur early as well (O'Day and Lal, 2010; Jovanovic et al., 2010).
Etiology The etiology is multifactorial with three major contributors to the development of breast cancer: 1) genetic factors, 2) hormonal influences and 3) environmental factors. Less than 10% of women with breast cancer have a family history of the disease (BRCA1/BRCA2 mutations, ATM, TP53). Hormonal influences include early menstruation, late menopause, nulliparity, and late age at first childbirth. Environmental risk factors include alcohol consumption and dietary fat intake. Cigarette smoking and caffeine consumption have not been implicated in breast cancer.
Epidemiology Worldwide, breast cancer is the most common invasive cancer in women. Incidence and mortality data on breast cancer can be found at the International Agency for Research on Cancer Globocan website and at the SEER database of the U.S. National Cancer Institute. Based on rates from 2006-2008, 12.29% (1/8) of women born today will be diagnosed with breast cancer at some time during their lifetime. Breast cancer is rarely found before the age of 25 years (except in familial cases). The incidence then increases with age, with most women being 60 years old when diagnosed.
The main risk factors are genetic predisposition, increasing age, proliferative breast disease, carcinoma of the contralateral breast or endometrium, radiation exposure (Hodgkin lymphoma), geographic influences, race, length of reproductive life, parity, age of first child (older than 30 years), obesity, and exogeneous estrogens (hormonal replacement therapy, oral contraceptives).
Clinics Cancers of the breast are usually first discovered by women or their physician as a solitary painless mass. The use of mammography, sonography and MRI has increased the detection of ductal carcinoma in situ (DCIS) and small invasive tumors before they reach palpable size. These non-palpable lesions can then be sampled by image-guided core needle biopsies. These lesions are usually <1 cm in size and less than 1/5th will have axillary metastases. Palpable lesions, in contrast, are usually 2-3 cm in size when first found, and approximately 1/3 has already spread to axillary or other lymph nodes. Lymph node status is generally assessed through the sentinel node procedure.

Clinical staging:
The American Joint Committee on Cancer (AJCC) staging system provides a strategy for grouping patients with respect to prognosis. Therapeutic decisions are formulated in part according to staging categories but primarily according to tumor size, lymph node status, estrogen-receptor and progesterone-receptor levels in the tumor tissue, human epidermal growth factor receptor 2 (HER-2/neu) status, menopausal status, and the general health of the patient (Edge et al., 2010). Stages are subdivided as follows:
- Stage 0: Ductal carcinoma in situ (DCIS) or lobular carcinoma in situ (LCIS); 5-year survival rate 93%
- Stage 1: Invasive carcinoma 2 cm or less without nodal involvement and no distant metastases; 5-year survival rate 88%
- Stage 2: Invasive carcinoma 5 cm or less with involved but movable axillary lymph nodes and no distant metastases, or a tumor > 5 cm without nodal involvement or distant metastases (5-year survival rate 74-81%)
- Stage 3 (locally advanced): Breast cancer > 5 cm with nodal involvement; or any breast cancer with fixed axillary nodes; or any breast cancer with involvement of the ipsilateral internal mammary lymph nodes; or any breast cancer with skin involvement, pectoral and chest wall fixation, edema, or clinical inflammatory carcinoma, if distant metastases are absent (5-year survival rate 41-67%)
- Stage 4: any form of breast cancer with distant metastases (including ipsilateral supraclavicular lymph nodes); 5-year survival rate 15%.

Pathology The pathologist assesses resection margins, lymph node status, tumor size, tumor grade, mitotic activity, histological subtype, lymphovascular invasion, hormonal receptor status (by immunohistochemistry) and HER2 status.
 
Figure 2: Breast cancer biomarkers. Top left: ERα expression. Top right: HER2 receptor overexpression (3+). Bottom left: Ki67/MIB1 nuclear expression. Bottom right: lymph node metastasis.
Treatment Surgery (mastectomy or lumpectomy, axillary node dissection), radiation, hormonal therapy, chemotherapy or combinations. A very important therapeutic strategy since 1998 is targeted therapy with trastuzumab, a humanized monoclonal antibody directed against the human epidermal growth factor receptor 2 (HER2, amplified and overexpressed in 10-15% of breast cancers) (Romond et al., 2005).
Prognosis Prognosis and survival rates vary greatly depending on cancer type, grade, proliferation rate (van Diest et al., 2004), staging and treatment. Prognosis of breast tumors without distant metastases depends on a number of histopathological factors (upon distant metastases, cure is unlikely):
- Locally advanced disease (skin or skeletal muscle invasion)
- Presence and number of lymph node metastases, including the size of metastatic deposit and invasion through the capsule
- Tumor size
- Histological subtype (NST/medullary/metaplastic vs. tubular, cribriform, mucinous)
- Tumor grade (Bloom and Richardson grading system combines tubule formation, mitotic rate and nuclear atypia)
- Hormonal receptor status (estrogen and progesterone receptor positivity confers better prognosis; 70-80% of breast cancers are positive for ER/PR)
- Proliferative rate (mitotic index, Ki-67 staining)
- Expression of certain oncogenes (HER2, MYC) or loss of tumor suppressor genes (TP53, CDH1).

Genetics

Note Most breast cancer cases are sporadic, with many different oncogenes and tumor suppressor genes involved, while 5-10% are estimated to be due to an inherited predisposition. Autosomal dominant alterations in two genes, BRCA1 and BRCA2, are likely to account for most familial cases of early-onset breast cancer, and for 3-4% of all breast cancers. Mutations in several other genes, including TP53, PTEN, STK11/LKB1, CDH1, CHEK2, ATM, MLH1, and MSH2, have also been associated with hereditary breast tumors (Campeau et al., 2008; Walsh et al., 2006).

Cytogenetics

Figure 3. Left: invasive breast carcinoma with HER2 amplification by CISH; Right: FISH showing invasive breast carcinoma with HER2 amplification (red) and CEP17 gain (green).
Cytogenetics Molecular Although traditionally classical karyotyping and chromosome based comparative genomic hybridization (CGH) have yielded information on chromosomal loci and genes involved in breast carcinogenesis, nowadays molecular and cytogenetic techniques such as fluorescence in situ hybridization (FISH, see Figure 3 right), (q)PCR, multiplex ligation-dependent probe amplification (MLPA, see Figure 4), next generation sequencing, and array techniques for CGH, gene expression, methylation and microRNAs are frequently used in breast cancer diagnostics and research.
FISH, as well as its chromogenic counterparts C(hromogenic)ISH and S(ilver)ISH, but also MLPA are currently used to analyze HER2 gene amplification status, an important prognostic factor and predictor of trastuzumab, chemotherapy and hormonal therapy response in breast cancer. ISH and MLPA are generally performed as a second-line gene amplification test in tumors for which the immunohistochemistry (protein expression) status for HER2 is equivocal (so-called 2+). Amplification of HER2 is usually determined as ratio of HER2 on CEP17, the centromere of chromosome 17 (where HER2 resides), to correct for a phenomenon called polysomy 17. However, several groups have questioned the value of CEP17 correction since it does not seem to be correlated to chromosome 17 polysomy, which in fact is very rare (Moelans et al., 2011).
CGH has mainly been used in the research setting because of its high costs and difficulty of interpretation. Results of CGH have extensively been described here, with most frequent alterations (mainly gains and amplifications) on chromosomes 8, 11 and 17. A graphical representation of the chromosomal aberrations found in breast tumors can be found here. A possible application for CGH in diagnostics in the future could be the differential diagnosis metastasis/new primary tumor. Genetic alterations in the primary tumor are believed to be fairly conserved throughout the metastatic process and as such, comparison of the chromosomal profiles of primary tumors and metastases should show high similarity.
Sequencing projects provide us with more insight in breast cancer genomic rearrangements (copy number alterations, breakpoints, intra- and inter-chromosomal rearrangements (Edgren et al., 2011). A graphical (Circos plot) representation of chromosomal rearrangements in the MCF7 breast cancer cell line can be found here, and illustrates the complexity of the breast cancer genome. A series of recent next-generation sequencing manuscripts have further underlined the genetic diversity of breast cancer. Beyond confirming recurrent somatic mutations in PIK3CA, TP53, AKT1, GATA3 and MAP3K1, potential driver mutations were identified in several new cancer genes including AKT2, ARID1B, CASP8, CDKN1B, MAP3K1, MAP3K13, NCOR1, SMARCD1, TBX3, MTAP, PPP2R2A, CBFB and MAP2K3 (Stephens et al., 2012; Banerji et al., 2012; Curtis et al., 2012). Next to recurrent mutations and deletions, recurrent fusion products have also been shown (Banerji et al., 2012) to be more or less present in certain subtypes of breast cancer. Analysis of paired DNA-RNA profiles revealed novel subgroups with distinct clinical outcomes (Curtis et al., 2012). As for most human cancers, aneuploidy is frequently present in breast tumors. The predictive value of nuclear DNA content in mammary carcinoma is still under debate in spite of several reports indicating a relationship between DNA ploidy and prognosis.
Chromosomal translocations that form fusion products and/or activate gene expression by promoter insertion are key events in hematological malignancies, but have been reported to be less common in epithelial cancers such as breast cancer. However, that view is currently being challenged by array painting and next generation sequencing studies. Reciprocal and more complex balanced translocations seem to be far more frequent than expected. The NRG1 gene on 8p12 seems to be translocated in 6% of breast cancers (Huang et al., 2004; Chua et al., 2009) and furthermore, several translocation break points are located within genes, including known cancer-critical genes such as EP300/p300 and CTCF (Howarth et al., 2008; Edwards, 2010). One of the best known translocations in a specific subtype of breast cancer (secretory type) is a recurrent chromosomal translocation t(12;15)(p13;q25), leading to the formation of the ETV6-NTRK3 fusion gene (Vasudev and Onuma, 2011). Another well-known recurrent translocation in adenoid cystic carcinoma (ACC) of the breast, t(6;9)(q22-23;p23-24), resulting in a fusion of the two transcription factor genes MYB and NFIB (Persson et al., 2009). The fusion results in loss of the 3'-end of MYB, including several conserved binding sites for microRNAs that regulate MYB expression negatively.
Figure 4. Top: HER2 non-amplified case by multiplex ligation-dependent probe amplification (MLPA). Bottom: HER2-amplified case by MLPA; notice the increased peak height for 5 probes (* = HER2 probes).

Genes involved and Proteins

Note The number of genetic alterations in breast cancer is immense and it is therefore not possible to elaborate on all of them. A selection was made based on the amount of evidence/literature present. Several of the genes/proteins involved in invasive ductal carcinoma have already been described in "Breast tumors: an overview". These will not be repeated here (TP53, HER2/ERBB2, CCND1, FGFR1, BRCA1, BRCA2, BRCA3, PTEN, ATM, MSH2, MLH1, PMS1, MSH3, CDH1, HRAS, NRAS and KRAS).
Gene Name BIRC5
Location 17q25
Protein The encoded protein (baculoviral IAP repeat containing 5), also called survivin, is an adapter molecule involved in signal transduction, cell communication and cell survival. It is a component of the chromosomal passenger complex (CPC), a complex that acts as a key regulator of mitosis. The BIRC5 gene is a member of the inhibitor of apoptosis (IAP) gene family, which encodes negative regulatory proteins that prevent apoptotic cell death. Amplification of the BIRC5 region (in 15-30% of breast cancers) has been shown to predict distant recurrence (Davis et al., 2007) and an altered cytoplasmic to nuclear ratio of BIRC5 was shown to be an independent prognostic factor in breast cancer (Brennan et al., 2008).

Gene Name EGFR
Location 7p11
Protein The epidermal growth factor receptor 1 (EGFR, ERBB1) is one of the four members of the ErbB family. EGFR is a receptor tyrosine kinase protein that binds to EGF. Binding to its ligand induces receptor dimerization, tyrosine autophosphorylation and leads to cell proliferation. EGFR is amplified in a small percentage (5-10%) of sporadic breast tumors but a broad range of amplification frequencies has been reported in literature (7-65%) (Lambros et al., 2007). EGFR amplification/overexpression is however more frequent in hereditary, triple negative (ER, PR and HER2 negative) and basal-like breast tumors (Livasy et al., 2006; van der Groep et al., 2004). As for IGFR1 (see below), one of the mechanisms of resistance to the HER2-targeted antibody trastuzumab is cross-talk between EGFR and HER2, which has lead to the development of a dual (oral) tyrosine kinase inhibitor of HER2 and EGFR, called lapatinib (Montemurro et al., 2007).

Gene Name EMSY
Location 11q13
Protein Its protein can repress transcription, possibly via its interaction with a multiprotein chromatin remodeling complex that modifies the chromatin. Its interaction with BRCA2 suggests that it may play a central role in the DNA repair function of BRCA2. It is amplified in 7-13% of breast tumors (Hughes-Davies et al., 2003; Kirkegaard et al., 2008; Moelans et al., 2010). Co-amplification of CCND1 and EMSY was shown to be associated with an adverse outcome in ER-positive tamoxifen-treated breast cancers (Brown et al., 2010). On the other hand, a recent study suggested that EMSY is unlikely to be a driver of the 11q13-q14 amplicon and does not have a dominant role in modulating the response to agents targeting cells with defective homologous recombination (Wilkerson et al., 2011).

Gene Name ESR1
Location 6q25.1
Protein This gene encodes an estrogen receptor (ER alpha), a ligand-activated transcription factor. Upon ligand binding the estrogen receptor undergoes a conformational change allowing dimerization to form either homo- or heterodimers. As a dimer, the estrogen receptor binds to the estrogen response element (ERE) in the promoter region of target genes. Initial reports showed an ESR1 amplification frequency of 20.6% in breast cancer (Holst et al., 2007) but subsequent studies reported considerably lower amplification frequencies, ranging between 5 and 10% (Albertson, 2008; Moelans et al., 2012). Studies have been contradictory with respect to its correlation with ER alpha protein overexpression, prognostic value as well as predictive value (tamoxifen response or resistance). ER alpha protein overexpression is present in 70-80% of breast cancers and is predictive of response to endocrine therapy (Wolmark and Dunn, 2001).

Gene Name HIF1A
Location 14q23.2
Protein This gene encodes the alpha subunit of transcription factor hypoxia-inducible factor-1 (HIF-1), which is a heterodimer composed of an alpha and a beta subunit. HIF-1 functions as a regulator of cellular response to hypoxia by activating transcription of many genes, including those involved in energy metabolism, angiogenesis and apoptosis. HIF-1 thus plays an essential role in tumor angiogenesis and survival (Semenza, 2000). Although no amplifications are involved (Vleugel et al., 2004), HIF1 alpha has been shown to be overexpressed in sporadic breast cancer, and even more in BRCA1-related hereditary breast cancer (van der Groep et al., 2008). Increased levels of HIF1 alpha have been associated independently with poor prognosis in lymph node negative breast carcinoma (Bos et al., 2003).

Gene Name IGF1R
Location 15q26.3
Protein Its protein is a receptor with tyrosine kinase activity. IGFRs mediate their intracellular actions through the PI3-K and RAS/RAF/MAPK signaling pathways. Many tumors have altered expression of IGF1R and its ligands and this constitutes an early event in tumorigenesis. IGF1R overexpression is predominantly seen in ER-positive breast tumors. The HER2 group (ER/PR negative, HER2 positive) generally shows reduced expression and the expression is somewhat heterogeneous in the triple-negative group (ER, PR and HER2 negative) (Bhargava et al., 2011).
One of the mechanisms of resistance to the HER2-targeted antibody trastuzumab is cross-talk between the insulin-like growth factor-I receptor and HER2 (Jin and Esteva, 2008). In addition to its therapeutic potential in HER2-positive trastuzumab-resistant tumors, targeting the IGF1R also shows therapeutic potential in basal-like breast cancers, a group of aggressive tumors of poor prognosis for which there is no effective targeted therapy currently available (Klinakis et al., 2009).

Gene Name MYC
Location 8q24
Protein c-myc is a nuclear protein that plays a role in cell cycle progression, apoptosis and cellular transformation. It functions as a transcription factor that regulates transcription of specific target genes. It is amplified in 9-15% of breast cancers but a broad range of amplification frequencies has been reported (between 1 and 94%) (Lambros et al., 2007; Jensen et al., 2009). MYC amplification has generally been associated with a worse prognosis, with higher mitotic activity and larger tumor size (Moelans et al., 2010). In human breast tumors, MYC amplification has been associated with HER2 amplification and HER2-amplified breast tumors were shown to have a 2.5-fold or greater increased likelihood of having MYC amplification (Al-Kuraya et al., 2004). Patients with MYC/HER2 co-amplification were observed to have substantially worse outcomes than patients who had single-gene amplification, even after standard chemotherapy. However, it was subsequently shown that patients with MYC/HER2 co-amplification in their primary breast tumors benefited significantly more from trastuzumab than did patients with only HER2 amplification. This could, however, not be confirmed in a later study (Perez et al., 2011).

Gene Name NOTCH1
Location 9q34.3
Protein Functions as a receptor for membrane-bound ligands Jagged1, Jagged2 and Delta1. Upon ligand activation through the released NOTCH1 intracellular domain (NICD) it forms a transcriptional activator complex. NOTCH1 affects multiple cellular processes including stem cell maintenance, cell fate, differentiation, proliferation, motility and survival (Reedijk, 2012). Aberrant NOTCH1 activity influences breast cancer progression through these processes and NOTCH1 activity seems to participate in cancer metastasis by modulating the EMT, angiogenesis, and anoikis-resistance of tumor cells (Hu et al., 2012). Aberrant NOTCH signaling can induce breast carcinoma in transgenic mice, and high expression of NOTCH receptors and ligands has been linked to poor clinical outcomes in patients with breast cancer (Han et al., 2011).

Gene Name PIK3CA
Location 3q26.3
Protein PI 3-Kinases (phosphoinositide 3-kinases, PI3Ks) coordinate a diverse range of cell functions including proliferation, cell survival, degranulation, vesicular trafficking and cell migration. PIK3CA activating mutations show a high prevalence in breast cancer (34%) (Cizkova et al., 2012) and are associated with higher age at diagnosis, hormone receptor positivity, HER2 negativity, lower tumor grade and stage, and lymph node negativity. PIK3CA mutations have been associated with significantly longer metastasis-free survival, especially in the PR-positive and HER2-positive subgroups (Cizkova et al., 2012). The majority of mutations occur at three hotspots, making these ideal targets for therapeutic development.

Gene Name PTEN
Location 10q23
Protein This gene was identified as a tumor suppressor that is mutated in a large number of cancers at high frequency. The protein encoded this gene is a phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase that antagonizes the PI3K-AKT/PKB signaling pathway and thereby modulates cell cycle progression and cell survival. About 25-50% of women with Cowden disease, a syndrome associated with germ-line mutations of the PTEN gene (at 10q23), develop breast cancer, but PTEN mutations have been found in only 5% of sporadic breast cancers. However, 29-48% of breast cancers display loss of heterozygosity in 10q23, about 40% of breast cancers show a decrease or absence of PTEN protein levels at the time of diagnosis (Garcia et al., 2004) and PTEN promoter hypermethylation was reported to be a common event in sporadic breast cancer, occurring in 20-50% of breast cancers (Khan et al., 2004).
PTEN not only antagonizes tumorigenesis but also sensitizes breast cancers to targeted therapy with trastuzumab (Pandolfi, 2004). Its loss has therefore been associated with trastuzumab resistance (Nahta and O'Regan, 2010).

Gene Name RARB
Location 3p24
Protein This receptor binds retinoic acid, the biologically active form of vitamin A which mediates cellular signalling in embryonic morphogenesis, cell growth and differentiation. RXR-RAR heterodimers act as ligand-dependent transcriptional regulators by binding to the specific retinoic acid response element (RARE) found in the promoter regions of target genes. In the absence of a RAR agonist, RXR-RAR recruits co-repressor proteins and associated factors such as histone deacetylases to maintain a condensed chromatin structure. RAR agonist binding stimulates co-repressor release and co-activator complexes, such as histone acetyltransferase, are recruited to activate transcription. The RARB2 promotor region was shown to be methylated in 20-25% of breast cancers and methylation was shown to be an independent important determinant of breast cancer prognosis (Sharma et al., 2009; Cho et al., 2012).

Gene Name RASSF1
Location 3p21.3
Protein This gene encodes a protein similar to the RAS effector proteins. Loss or altered expression of this gene has been associated with a variety of cancers, which suggests a tumor suppressor function. The inactivation of this gene was found to be correlated with the hypermethylation of its CpG-island promoter region. The encoded protein was found to interact with DNA repair proteins and was also shown to inhibit the accumulation of cyclin D1, and thus induce cell cycle arrest. The most important isoform for breast cancer seems to be isoform A. The frequency of RASSF1A methylation in breast tumors is high (65%) and methylation in tumor samples and fine-needle aspirate washings was shown to be an independent predictor of poor prognosis (Sharma et al., 2009; Buhmeida et al., 2011; Martins et al., 2011). RASSF1A methylation is an attractive biomarker for early cancer detection and its methylation analysis is applicable to a range of body fluids including serum and nipple fluid (Suijkerbuijk et al., 2008).

Gene Name SRC
Location 20q12-q13
Protein The protein encoded by this gene is a non-receptor protein tyrosine kinase that plays pivotal roles in numerous cellular processes such as proliferation, migration, and transformation. Src kinases are key upstream mediators of both the PI3-K and MAPK signaling pathways, and have been shown to have important roles in cell proliferation, migration and survival. c-SRC (SRC) is a key modulator of trastuzumab response and a common node downstream of multiple trastuzumab resistance pathways (Zhang et al., 2011). SRC is activated in both acquired and de novo trastuzumab-resistant cells and regulation involves dephosphorylation by PTEN. Increased SRC activation conferred considerable trastuzumab resistance in breast cancer cells and correlated with trastuzumab resistance in patients. Targeting SRC in combination with trastuzumab sensitized multiple lines of trastuzumab-resistant cells to trastuzumab and eliminated trastuzumab-resistant tumors in vivo, suggesting the potential clinical application of this strategy to overcome trastuzumab resistance (Zhang et al., 2011). Furthermore, early-phase clinical trials using the src-inhibitors dasatinib and bosutinib have suggested modest activity as monotherapy in breast cancer, with potentially greater activity in combination regimens. Given the interaction between SRC and the estrogen receptor, ongoing trials are exploring combinations with endocrine therapy. The relationship between SRC and the vascular endothelial growth factor receptor also justifies investigation of combinations with angiogenesis inhibitors (Mayer and Krop, 2010).

Gene Name TOP2A
Location 17q21-q22
Protein This gene encodes a DNA topoisomerase, an enzyme that controls and alters the topologic states of DNA during transcription. This nuclear enzyme is involved in processes such as chromosome condensation, chromatid separation, and the relief of torsional stress that occurs during DNA transcription and replication. It catalyzes the transient breaking and rejoining of two strands of duplex DNA which allows the strands to pass through one another, thus altering the topology of DNA. It is amplified in 5-10 % of breast tumors but amplification is not correlated with overexpression (Di Leo et al., 2002; Knoop et al., 2005; Moelans et al., 2010). TOP2A has been suggested to be a predictive marker of anthracyclin benefit (Nielsen et al., 2008) but subsequent studies were controversial (Bartlett et al., 2010).

Gene Name TWIST1
Location 7p21
Protein TWIST1 is a basic helix loop helix protein that plays a role both in human development and in cancer biogenesis. It is an anti-apoptotic and pro-metastatic transcription factor that is known to repress E-cadherin expression in breast cancer (Vesuna et al., 2008) as well as ERα expression thereby contributing to the development of hormone resistance (Vesuna et al., 2012). It is overexpressed in many epithelial cancers including breast cancer. Twist overexpression in breast cancer cells can induce angiogenesis, correlates with chromosomal instability, and promotes an epithelial-mesenchymal-like transition (EMT) that is pivotal for the transformation into an aggressive breast cancer phenotype (Mironchik et al., 2005). TWIST1 promoter methylation is significantly more prevalent in malignant compared with healthy breast tissue and is therefore useful as a biomarker in breast cancer diagnosis, although there is no direct correlation with TWIST1 expression (Gort et al., 2008).

Bibliography

Prognostic relevance of gene amplifications and coamplifications in breast cancer.
Al-Kuraya K, Schraml P, Torhorst J, Tapia C, Zaharieva B, Novotny H, Spichtin H, Maurer R, Mirlacher M, Kochli O, Zuber M, Dieterich H, Mross F, Wilber K, Simon R, Sauter G.
Cancer Res. 2004 Dec 1;64(23):8534-40.
PMID 15574759
 
Conflicting evidence on the frequency of ESR1 amplification in breast cancer.
Albertson DG.
Nat Genet. 2008 Jul;40(7):821-2. doi: 10.1038/ng0708-821.
PMID 18583976
 
Sequence analysis of mutations and translocations across breast cancer subtypes.
Banerji S, Cibulskis K, Rangel-Escareno C, Brown KK, Carter SL, Frederick AM, Lawrence MS, Sivachenko AY, Sougnez C, Zou L, Cortes ML, Fernandez-Lopez JC, Peng S, Ardlie KG, Auclair D, Bautista-Pina V, Duke F, Francis J, Jung J, Maffuz-Aziz A, Onofrio RC, Parkin M, Pho NH, Quintanar-Jurado V, Ramos AH, Rebollar-Vega R, Rodriguez-Cuevas S, Romero-Cordoba SL, Schumacher SE, Stransky N, Thompson KM, Uribe-Figueroa L, Baselga J, Beroukhim R, Polyak K, Sgroi DC, Richardson AL, Jimenez-Sanchez G, Lander ES, Gabriel SB, Garraway LA, Golub TR, Melendez-Zajgla J, Toker A, Getz G, Hidalgo-Miranda A, Meyerson M.
Nature. 2012 Jun 20;486(7403):405-9. doi: 10.1038/nature11154.
PMID 22722202
 
Predictive markers of anthracycline benefit: a prospectively planned analysis of the UK National Epirubicin Adjuvant Trial (NEAT/BR9601).
Bartlett JM, Munro AF, Dunn JA, McConkey C, Jordan S, Twelves CJ, Cameron DA, Thomas J, Campbell FM, Rea DW, Provenzano E, Caldas C, Pharoah P, Hiller L, Earl H, Poole CJ.
Lancet Oncol. 2010 Mar;11(3):266-74. doi: 10.1016/S1470-2045(10)70006-1. Epub 2010 Jan 13.
PMID 20079691
 
Insulin-like growth factor receptor-1 (IGF-1R) expression in normal breast, proliferative breast lesions, and breast carcinoma.
Bhargava R, Beriwal S, McManus K, Dabbs DJ.
Appl Immunohistochem Mol Morphol. 2011 May;19(3):218-25. doi: 10.1097/PAI.0b013e3181ffc58c.
PMID 21217522
 
Levels of hypoxia-inducible factor-1alpha independently predict prognosis in patients with lymph node negative breast carcinoma.
Bos R, van der Groep P, Greijer AE, Shvarts A, Meijer S, Pinedo HM, Semenza GL, van Diest PJ, van der Wall E.
Cancer. 2003 Mar 15;97(6):1573-81.
PMID 12627523
 
Altered cytoplasmic-to-nuclear ratio of survivin is a prognostic indicator in breast cancer.
Brennan DJ, Rexhepaj E, O'Brien SL, McSherry E, O'Connor DP, Fagan A, Culhane AC, Higgins DG, Jirstrom K, Millikan RC, Landberg G, Duffy MJ, Hewitt SM, Gallagher WM.
Clin Cancer Res. 2008 May 1;14(9):2681-9. doi: 10.1158/1078-0432.CCR-07-1760.
PMID 18451232
 
Co-amplification of CCND1 and EMSY is associated with an adverse outcome in ER-positive tamoxifen-treated breast cancers.
Brown LA, Johnson K, Leung S, Bismar TA, Benitez J, Foulkes WD, Huntsman DG.
Breast Cancer Res Treat. 2010 Jun;121(2):347-54. doi: 10.1007/s10549-009-0479-x. Epub 2009 Jul 28.
PMID 19636701
 
Genetic relation of lobular carcinoma in situ, ductal carcinoma in situ, and associated invasive carcinoma of the breast.
Buerger H, Simon R, Schafer KL, Diallo R, Littmann R, Poremba C, van Diest PJ, Dockhorn-Dworniczak B, Bocker W.
Mol Pathol. 2000 Jun;53(3):118-21.
PMID 10897329
 
RASSF1A methylation is predictive of poor prognosis in female breast cancer in a background of overall low methylation frequency.
Buhmeida A, Merdad A, Al-Maghrabi J, Al-Thobaiti F, Ata M, Bugis A, Syrjanen K, Abuzenadah A, Chaudhary A, Gari M, Al-Qahtani M, Dallol A.
Anticancer Res. 2011 Sep;31(9):2975-81.
PMID 21868547
 
Hereditary breast cancer: new genetic developments, new therapeutic avenues.
Campeau PM, Foulkes WD, Tischkowitz MD.
Hum Genet. 2008 Aug;124(1):31-42. doi: 10.1007/s00439-008-0529-1. Epub 2008 Jun 25. (REVIEW)
PMID 18575892
 
Prognostic significance of gene-specific promoter hypermethylation in breast cancer patients.
Cho YH, Shen J, Gammon MD, Zhang YJ, Wang Q, Gonzalez K, Xu X, Bradshaw PT, Teitelbaum SL, Garbowski G, Hibshoosh H, Neugut AI, Chen J, Santella RM.
Breast Cancer Res Treat. 2012 Jan;131(1):197-205. doi: 10.1007/s10549-011-1712-y. Epub 2011 Aug 12.
PMID 21837480
 
The NRG1 gene is frequently silenced by methylation in breast cancers and is a strong candidate for the 8p tumour suppressor gene.
Chua YL, Ito Y, Pole JC, Newman S, Chin SF, Stein RC, Ellis IO, Caldas C, O'Hare MJ, Murrell A, Edwards PA.
Oncogene. 2009 Nov 19;28(46):4041-52. doi: 10.1038/onc.2009.259. Epub 2009 Oct 5.
PMID 19802002
 
PIK3CA mutation impact on survival in breast cancer patients and in ERalpha, PR and ERBB2-based subgroups.
Cizkova M, Susini A, Vacher S, Cizeron-Clairac G, Andrieu C, Driouch K, Fourme E, Lidereau R, Bieche I.
Breast Cancer Res. 2012 Feb 13;14(1):R28.
PMID 22330809
 
The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups.
Curtis C, Shah SP, Chin SF, Turashvili G, Rueda OM, Dunning MJ, Speed D, Lynch AG, Samarajiwa S, Yuan Y, Graf S, Ha G, Haffari G, Bashashati A, Russell R, McKinney S; METABRIC Group, Langerod A, Green A, Provenzano E, Wishart G, Pinder S, Watson P, Markowetz F, Murphy L, Ellis I, Purushotham A, Borresen-Dale AL, Brenton JD, Tavare S, Caldas C, Aparicio S.
Nature. 2012 Apr 18;486(7403):346-52. doi: 10.1038/nature10983.
PMID 22522925
 
Amplification patterns of three genomic regions predict distant recurrence in breast carcinoma.
Davis LM, Harris C, Tang L, Doherty P, Hraber P, Sakai Y, Bocklage T, Doeden K, Hall B, Alsobrook J, Rabinowitz I, Williams TM, Hozier J.
J Mol Diagn. 2007 Jul;9(3):327-36.
PMID 17591932
 
HER-2 amplification and topoisomerase IIalpha gene aberrations as predictive markers in node-positive breast cancer patients randomly treated either with an anthracycline-based therapy or with cyclophosphamide, methotrexate, and 5-fluorouracil.
Di Leo A, Gancberg D, Larsimont D, Tanner M, Jarvinen T, Rouas G, Dolci S, Leroy JY, Paesmans M, Isola J, Piccart MJ.
Clin Cancer Res. 2002 May;8(5):1107-16.
PMID 12006526
 
Breast.
Edge SB, Byrd DR, Compton CC, et al.
AJCC Cancer Staging Manual. 7th ed. New York, NY; Springer. 2010;347-76.
 
Identification of fusion genes in breast cancer by paired-end RNA-sequencing.
Edgren H, Murumagi A, Kangaspeska S, Nicorici D, Hongisto V, Kleivi K, Rye IH, Nyberg S, Wolf M, Borresen-Dale AL, Kallioniemi O.
Genome Biol. 2011;12(1):R6. doi: 10.1186/gb-2011-12-1-r6. Epub 2011 Jan 19.
PMID 21247443
 
Fusion genes and chromosome translocations in the common epithelial cancers.
Edwards PA.
J Pathol. 2010 Jan;220(2):244-54. doi: 10.1002/path.2632. (REVIEW)
PMID 19921709
 
Promoter methylation of the PTEN gene is a common molecular change in breast cancer.
Garcia JM, Silva J, Pena C, Garcia V, Rodriguez R, Cruz MA, Cantos B, Provencio M, Espana P, Bonilla F.
Genes Chromosomes Cancer. 2004 Oct;41(2):117-24.
PMID 15287024
 
Methylation of the TWIST1 promoter, TWIST1 mRNA levels, and immunohistochemical expression of TWIST1 in breast cancer.
Gort EH, Suijkerbuijk KP, Roothaan SM, Raman V, Vooijs M, van der Wall E, van Diest PJ.
Cancer Epidemiol Biomarkers Prev. 2008 Dec;17(12):3325-30. doi: 10.1158/1055-9965.EPI-08-0472.
PMID 19064546
 
Notch signaling as a therapeutic target for breast cancer treatment?
Han J, Hendzel MJ, Allalunis-Turner J.
Breast Cancer Res. 2011 May 31;13(3):210. doi: 10.1186/bcr2875. (REVIEW)
PMID 21672271
 
On the evidence for ESR1 amplification in breast cancer.
Holst F, Moelans CB, Filipits M, Singer CF, Simon R, van Diest PJ.
Nat Rev Cancer. 2012 Jan 24;12(2):149. doi: 10.1038/nrc3093-c3.
PMID 22270954
 
Estrogen receptor alpha (ESR1) gene amplification is frequent in breast cancer.
Holst F, Stahl PR, Ruiz C, Hellwinkel O, Jehan Z, Wendland M, Lebeau A, Terracciano L, Al-Kuraya K, Janicke F, Sauter G, Simon R.
Nat Genet. 2007 May;39(5):655-60. Epub 2007 Apr 8.
PMID 17417639
 
Array painting reveals a high frequency of balanced translocations in breast cancer cell lines that break in cancer-relevant genes.
Howarth KD, Blood KA, Ng BL, Beavis JC, Chua Y, Cooke SL, Raby S, Ichimura K, Collins VP, Carter NP, Edwards PA.
Oncogene. 2008 May 22;27(23):3345-59. Epub 2007 Dec 17.
PMID 18084325
 
Notch signaling pathway and cancer metastasis.
Hu YY, Zheng MH, Zhang R, Liang YM, Han H.
Adv Exp Med Biol. 2012;727:186-98. doi: 10.1007/978-1-4614-0899-4_14. (REVIEW)
PMID 22399348
 
A recurrent chromosome breakpoint in breast cancer at the NRG1/neuregulin 1/heregulin gene.
Huang HE, Chin SF, Ginestier C, Bardou VJ, Adelaide J, Iyer NG, Garcia MJ, Pole JC, Callagy GM, Hewitt SM, Gullick WJ, Jacquemier J, Caldas C, Chaffanet M, Birnbaum D, Edwards PA.
Cancer Res. 2004 Oct 1;64(19):6840-4.
PMID 15466169
 
EMSY links the BRCA2 pathway to sporadic breast and ovarian cancer.
Hughes-Davies L, Huntsman D, Ruas M, Fuks F, Bye J, Chin SF, Milner J, Brown LA, Hsu F, Gilks B, Nielsen T, Schulzer M, Chia S, Ragaz J, Cahn A, Linger L, Ozdag H, Cattaneo E, Jordanova ES, Schuuring E, Yu DS, Venkitaraman A, Ponder B, Doherty A, Aparicio S, Bentley D, Theillet C, Ponting CP, Caldas C, Kouzarides T.
Cell. 2003 Nov 26;115(5):523-35.
PMID 14651845
 
Patterns of chromosomal alterations in breast ductal carcinoma in situ.
Hwang ES, DeVries S, Chew KL, Moore DH 2nd, Kerlikowske K, Thor A, Ljung BM, Waldman FM.
Clin Cancer Res. 2004 Aug 1;10(15):5160-7.
PMID 15297420
 
Frequent amplifications and deletions of G1/S-phase transition genes, CCND1 and MYC in early breast cancers: a potential role in G1/S escape.
Jensen LB, Bartlett JM, Witton CJ, Kirkegaard T, Brown S, Muller S, Campbell F, Cooke TG, Nielsen KV.
Cancer Biomark. 2009;5(1):41-9. doi: 10.3233/CBM-2009-0570.
PMID 19242061
 
Cross-talk between the ErbB/HER family and the type I insulin-like growth factor receptor signaling pathway in breast cancer.
Jin Q, Esteva FJ.
J Mammary Gland Biol Neoplasia. 2008 Dec;13(4):485-98. doi: 10.1007/s10911-008-9107-3. Epub 2008 Nov 25. (REVIEW)
PMID 19034632
 
The epigenetics of breast cancer.
Jovanovic J, Ronneberg JA, Tost J, Kristensen V.
Mol Oncol. 2010 Jun;4(3):242-54. doi: 10.1016/j.molonc.2010.04.002. Epub 2010 Apr 29. (REVIEW)
PMID 20627830
 
PTEN promoter is methylated in a proportion of invasive breast cancers.
Khan S, Kumagai T, Vora J, Bose N, Sehgal I, Koeffler PH, Bose S.
Int J Cancer. 2004 Nov 10;112(3):407-10.
PMID 15382065
 
Genetic alterations of CCND1 and EMSY in breast cancers.
Kirkegaard T, Nielsen KV, Jensen LB, Campbell FM, Muller S, Tovey SM, Brown S, Cooke TG, Bartlett JM.
Histopathology. 2008 May;52(6):698-705. doi: 10.1111/j.1365-2559.2008.03007.x. Epub 2008 Apr 2.
PMID 18393977
 
Igf1r as a therapeutic target in a mouse model of basal-like breast cancer.
Klinakis A, Szabolcs M, Chen G, Xuan S, Hibshoosh H, Efstratiadis A.
Proc Natl Acad Sci U S A. 2009 Feb 17;106(7):2359-64. doi: 10.1073/pnas.0810221106. Epub 2009 Jan 27.
PMID 19174523
 
Retrospective analysis of topoisomerase IIa amplifications and deletions as predictive markers in primary breast cancer patients randomly assigned to cyclophosphamide, methotrexate, and fluorouracil or cyclophosphamide, epirubicin, and fluorouracil: Danish Breast Cancer Cooperative Group.
Knoop AS, Knudsen H, Balslev E, Rasmussen BB, Overgaard J, Nielsen KV, Schonau A, Gunnarsdottir K, Olsen KE, Mouridsen H, Ejlertsen B; Danish Breast Cancer Cooperative Group.
J Clin Oncol. 2005 Oct 20;23(30):7483-90.
PMID 16234514
 
Chromogenic and fluorescent in situ hybridization in breast cancer.
Lambros MB, Natrajan R, Reis-Filho JS.
Hum Pathol. 2007 Aug;38(8):1105-22. (REVIEW)
PMID 17640550
 
Phenotypic evaluation of the basal-like subtype of invasive breast carcinoma.
Livasy CA, Karaca G, Nanda R, Tretiakova MS, Olopade OI, Moore DT, Perou CM.
Mod Pathol. 2006 Feb;19(2):264-71.
PMID 16341146
 
High RASSF1A promoter methylation levels are predictive of poor prognosis in fine-needle aspirate washings of breast cancer lesions.
Martins AT, Monteiro P, Ramalho-Carvalho J, Costa VL, Dinis-Ribeiro M, Leal C, Henrique R, Jeronimo C.
Breast Cancer Res Treat. 2011 Aug;129(1):1-9. doi: 10.1007/s10549-010-1160-0. Epub 2010 Sep 15.
PMID 20842524
 
Advances in targeting SRC in the treatment of breast cancer and other solid malignancies.
Mayer EL, Krop IE.
Clin Cancer Res. 2010 Jul 15;16(14):3526-32. doi: 10.1158/1078-0432.CCR-09-1834. (REVIEW)
PMID 20634194
 
Twist overexpression induces in vivo angiogenesis and correlates with chromosomal instability in breast cancer.
Mironchik Y, Winnard PT Jr, Vesuna F, Kato Y, Wildes F, Pathak AP, Kominsky S, Artemov D, Bhujwalla Z, Van Diest P, Burger H, Glackin C, Raman V.
Cancer Res. 2005 Dec 1;65(23):10801-9.
PMID 16322226
 
Implications of rarity of chromosome 17 polysomy in breast cancer.
Moelans CB, Reis-Filho JS, van Diest PJ.
Lancet Oncol. 2011 Nov;12(12):1087-9. doi: 10.1016/S1470-2045(11)70234-0. Epub 2011 Sep 6.
PMID 21903472
 
Similarity in expression of cell cycle proteins between in situ and invasive ductal breast lesions of same differentiation grade.
Mommers EC, Leonhart AM, Falix F, Michalides R, Meijer CJ, Baak JP, Diest PJ.
J Pathol. 2001 Jul;194(3):327-33.
PMID 11439365
 
Lapatinib: a dual inhibitor of EGFR and HER2 tyrosine kinase activity.
Montemurro F, Valabrega G, Aglietta M.
Expert Opin Biol Ther. 2007 Feb;7(2):257-68. (REVIEW)
PMID 17250463
 
Evolving strategies for overcoming resistance to HER2-directed therapy: targeting the PI3K/Akt/mTOR pathway.
Nahta R, O'Regan RM.
Clin Breast Cancer. 2010 Nov;10 Suppl 3:S72-8. doi: 10.3816/CBC.2010.s.015. (REVIEW)
PMID 21115425
 
The value of TOP2A gene copy number variation as a biomarker in breast cancer: Update of DBCG trial 89D.
Nielsen KV, Ejlertsen B, Moller S, Jorgensen JT, Knoop A, Knudsen H, Mouridsen HT.
Acta Oncol. 2008;47(4):725-34. doi: 10.1080/02841860801995396.
PMID 18465341
 
MicroRNAs and their target gene networks in breast cancer.
O'Day E, Lal A.
Breast Cancer Res. 2010;12(2):201. doi: 10.1186/bcr2484. Epub 2010 Mar 19. (REVIEW)
PMID 20346098
 
Breast cancer--loss of PTEN predicts resistance to treatment.
Pandolfi PP.
N Engl J Med. 2004 Nov 25;351(22):2337-8.
PMID 15564551
 
C-MYC alterations and association with patient outcome in early-stage HER2-positive breast cancer from the north central cancer treatment group N9831 adjuvant trastuzumab trial.
Perez EA, Jenkins RB, Dueck AC, Wiktor AE, Bedroske PP, Anderson SK, Ketterling RP, Sukov WR, Kanehira K, Chen B, Geiger XJ, Andorfer CA, McCullough AE, Davidson NE, Martino S, Sledge GW, Kaufman PA, Kutteh LA, Gralow JR, Harris LN, Ingle JN, Lingle WL, Reinholz MM.
J Clin Oncol. 2011 Feb 20;29(6):651-9. doi: 10.1200/JCO.2010.30.2125. Epub 2011 Jan 18.
PMID 21245420
 
Recurrent fusion of MYB and NFIB transcription factor genes in carcinomas of the breast and head and neck.
Persson M, Andren Y, Mark J, Horlings HM, Persson F, Stenman G.
Proc Natl Acad Sci U S A. 2009 Nov 3;106(44):18740-4. doi: 10.1073/pnas.0909114106. Epub 2009 Oct 19.
PMID 19841262
 
Notch signaling and breast cancer.
Reedijk M.
Adv Exp Med Biol. 2012;727:241-57. doi: 10.1007/978-1-4614-0899-4_18. (REVIEW)
PMID 22399352
 
Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer.
Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, Tan-Chiu E, Martino S, Paik S, Kaufman PA, Swain SM, Pisansky TM, Fehrenbacher L, Kutteh LA, Vogel VG, Visscher DW, Yothers G, Jenkins RB, Brown AM, Dakhil SR, Mamounas EP, Lingle WL, Klein PM, Ingle JN, Wolmark N.
N Engl J Med. 2005 Oct 20;353(16):1673-84.
PMID 16236738
 
C-myc, not HER-2/neu, can predict recurrence and mortality of patients with node-negative breast cancer.
Schlotter CM, Vogt U, Bosse U, Mersch B, Wassmann K.
Breast Cancer Res. 2003;5(2):R30-6. Epub 2003 Jan 13.
PMID 12631396
 
HIF-1: using two hands to flip the angiogenic switch.
Semenza GL.
Cancer Metastasis Rev. 2000;19(1-2):59-65.
PMID 11191064
 
Prognostic relevance of promoter hypermethylation of multiple genes in breast cancer patients.
Sharma G, Mirza S, Yang YH, Parshad R, Hazrah P, Datta Gupta S, Ralhan R.
Cell Oncol. 2009;31(6):487-500. doi: 10.3233/CLO-2009-0507.
PMID 19940364
 
The landscape of cancer genes and mutational processes in breast cancer.
Stephens PJ, Tarpey PS, Davies H, Van Loo P, Greenman C, Wedge DC, Nik-Zainal S, Martin S, Varela I, Bignell GR, Yates LR, Papaemmanuil E, Beare D, Butler A, Cheverton A, Gamble J, Hinton J, Jia M, Jayakumar A, Jones D, Latimer C, Lau KW, McLaren S, McBride DJ, Menzies A, Mudie L, Raine K, Rad R, Chapman MS, Teague J, Easton D, Langerod A; Oslo Breast Cancer Consortium (OSBREAC), Lee MT, Shen CY, Tee BT, Huimin BW, Broeks A, Vargas AC, Turashvili G, Martens J, Fatima A, Miron P, Chin SF, Thomas G, Boyault S, Mariani O, Lakhani SR, van de Vijver M, van 't Veer L, Foekens J, Desmedt C, Sotiriou C, Tutt A, Caldas C, Reis-Filho JS, Aparicio SA, Salomon AV, Borresen-Dale AL, Richardson AL, Campbell PJ, Futreal PA, Stratton MR.
Nature. 2012 May 16;486(7403):400-4. doi: 10.1038/nature11017.
PMID 22722201
 
Molecular analysis of nipple fluid for breast cancer screening.
Suijkerbuijk KP, van der Wall E, Vooijs M, van Diest PJ.
Pathobiology. 2008;75(2):149-52. doi: 10.1159/000123853. Epub 2008 Jun 10. (REVIEW)
PMID 18544970
 
Secretory breast carcinoma: unique, triple-negative carcinoma with a favorable prognosis and characteristic molecular expression.
Vasudev P, Onuma K.
Arch Pathol Lab Med. 2011 Dec;135(12):1606-10. doi: 10.5858/arpa.2010-0351-RS. (REVIEW)
PMID 22129193
 
Twist contributes to hormone resistance in breast cancer by downregulating estrogen receptor-alpha.
Vesuna F, Lisok A, Kimble B, Domek J, Kato Y, van der Groep P, Artemov D, Kowalski J, Carraway H, van Diest P, Raman V.
Oncogene. 2012 Jul 5;31(27):3223-34. doi: 10.1038/onc.2011.483. Epub 2011 Nov 7.
PMID 22056872
 
Twist is a transcriptional repressor of E-cadherin gene expression in breast cancer.
Vesuna F, van Diest P, Chen JH, Raman V.
Biochem Biophys Res Commun. 2008 Mar 7;367(2):235-41. Epub 2007 Dec 4.
PMID 18062917
 
No amplifications of hypoxia-inducible factor-1alpha gene in invasive breast cancer: a tissue microarray study.
Vleugel MM, Bos R, Buerger H, van der Groep P, Saramaki OR, Visakorpi T, van der Wall E, van Diest PJ.
Cell Oncol. 2004;26(5-6):347-51.
PMID 15623945
 
Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer.
Walsh T, Casadei S, Coats KH, Swisher E, Stray SM, Higgins J, Roach KC, Mandell J, Lee MK, Ciernikova S, Foretova L, Soucek P, King MC.
JAMA. 2006 Mar 22;295(12):1379-88.
PMID 16551709
 
Functional characterization of EMSY gene amplification in human cancers.
Wilkerson PM, Dedes KJ, Wetterskog D, Mackay A, Lambros MB, Mansour M, Frankum J, Lord CJ, Natrajan R, Ashworth A, Reis-Filho JS.
J Pathol. 2011 Sep;225(1):29-42. doi: 10.1002/path.2944. Epub 2011 Jul 7.
PMID 21735447
 
The role of tamoxifen in breast cancer prevention: issues sparked by the NSABP Breast Cancer Prevention Trial (P-1).
Wolmark N, Dunn BK.
Ann N Y Acad Sci. 2001 Dec;949:99-108.
PMID 11795386
 
Combating trastuzumab resistance by targeting SRC, a common node downstream of multiple resistance pathways.
Zhang S, Huang WC, Li P, Guo H, Poh SB, Brady SW, Xiong Y, Tseng LM, Li SH, Ding Z, Sahin AA, Esteva FJ, Hortobagyi GN, Yu D.
Nat Med. 2011 Apr;17(4):461-9. doi: 10.1038/nm.2309. Epub 2011 Mar 13.
PMID 21399647
 
Prognostic value of proliferation in invasive breast cancer: a review.
van Diest PJ, van der Wall E, Baak JP.
J Clin Pathol. 2004 Jul;57(7):675-81. (REVIEW)
PMID 15220356
 
High frequency of HIF-1alpha overexpression in BRCA1 related breast cancer.
van der Groep P, Bouter A, Menko FH, van der Wall E, van Diest PJ.
Breast Cancer Res Treat. 2008 Oct;111(3):475-80. Epub 2007 Nov 21.
PMID 18030615
 

Citation

This paper should be referenced as such :
Moelans, CB ; van, Diest PJ
Breast: Ductal carcinoma
Atlas Genet Cytogenet Oncol Haematol. 2013;17(3):209-220.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Tumors/DuctCarcBreastID5593.html


Other genes implicated (Data extracted from papers in the Atlas) [ 56 ]

Genes ADAM23 AKR1C3 ASH2L BCL2L14 CADM4 CAV1 CDK20 CD151 CD44 CDH3
CEACAM1 COL1A2 CPM CSE1L CTCF DLG1 EDIL3 EPAS1 EPB41L3 ERBB3
EZH2 FABP7 FAU FOXC1 FXYD3 HELLS HSPB8 KIF14 LIMK1 LOX
MST1 NMT1 NTSR1 PAK1 PARVB PIWIL2 PLAUR PSEN2 PTK2
PTK6 PTPN1 RHOBTB2 RPA2 S100A4 S100A7 S100A8 S100A9 SIAH2 SIRT1
SNCG TGFBR2 TGFBR3 TJP2 TWIST2 VTCN1

Translocations implicated (Data extracted from papers in the Atlas)

 t(12;15)(p13;q25) ETV6/NTRK3
 t(6;9)(q23;p24) MYB/NFIB

External links

Mitelman database t(12;15)(p13;q25) ETV6/NTRK3 [Case List]    t(12;15)(p13;q25) ETV6/NTRK3 [Association List] Mitelman database (CGAP - NCBI)
Mitelman database t(6;9)(q23;p24) MYB/NFIB [Case List]    t(6;9)(q23;p24) MYB/NFIB [Association List] Mitelman database (CGAP - NCBI)
arrayMap Topo ( C50) arrayMap ((UZH-SIB Zurich)   [auto + random 100 samples .. if exist ]   [tabulated segments]
 
Mitelman databaseETV6/NTRK3[MCList]    ETV6 (12p13.2) NTRK3 (15q25.3)   ins(12;15)(p13;q22q25)
TCGA_FusionETV6/NTRK3    ETV6 (12p13.2) NTRK3 (15q25.3)
TICdbETV6/NTRK3    ETV6 (12p13.2) NTRK3 (15q25.3)
Mitelman databaseMYB/NFIB[MCList]    MYB (6q23.3) NFIB (9p23)   t(6;9)(q23;p22)
TCGA_FusionMYB/NFIB    MYB (6q23.3) NFIB (9p23)
TICdbMYB/NFIB    MYB (6q23.3) NFIB (9p23)
 
Other databaseInternational agency for research on cancer (world health organisation), the Globocan project (2008)
Other databaseAJCC Cancer Staging Manual, 7th edition, updated Cancer staging Posters
Other databaseThe National Cancer Institute PDQ® Genetics of Breast and Ovarian Cancer (last modified 02/17/2012)
Other databaseICGC Data Portal - [BRCA-US] Breast Cancer - TCGA, US
Other databaseBreast invasive carcinoma (BRCA) TCGA Copy Number Portal
Other databaseBreast Invasive Carcinoma [ Genomic Data Commons - NCI TCGA-BRCA]
Disease databaseBreast: Ductal carcinoma
REVIEW articlesautomatic search in PubMed
Last year articlesautomatic search in PubMed


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