BCAR1 (breast cancer anti-estrogen resistance 1)

2011-12-01   Allison Berrier 

Department of Oral, Craniofacial Biology, LSUHSC-NO School of Dentistry, 1100 Florida Avenue, Clinical Bldg, Room 8301, New Orleans, LA 70119, USA




Atlas Image
Figure 1.



BCAR1 isoforms
Isoform 1: 916 aa, calc MW= 97,7 kDa. Isoform 2: 888 aa, (alternate 5 sequence compared to variant 1) calc MW= 95,1 kDa. Isoform 3: 888 aa, (alternate 5 sequence compared to variant 1) calc MW= 95,3 kDa. Isoform 4: 888 aa, (alternate 5 sequence and alternate splice site in the substrate domain compared to variant 1 resulting in a different N-terminus and additional segment in the middle region compared to isoform 1) calc MW= 95,3 kDa. Isoform 5: 870 aa, (lacks an exon in the 5 region, alternate AUG start codon, has a different N-terminus compared to isoform 1) calc MW= 93,16 kDa. Isoform 6: 870 aa, (different N-terminus compared to isoform 1) calc MW= 93,2 kDa. Isoform 7, 868 aa (shorter, alternate 5 sequence, different N-terminus compared to isoform 1) calc MW= 93 kDa. Isoform 8, 722 aa, (alternate internal sequence compared to isoform 1, different N-terminus compared to isoform 1) calc MW= 77,6 kDa. Isoform 9: 660 aa, (shorter alternate 5 sequence, different N-terminus compared to isoform 1) calc MW= 70,7 kDa.

BCAR proteins migrate during SDS-PAGE electrophoresis at a significantly higher molecular weight than predicted from sequence analysis perhaps due to the extensive phosphorylation of BCAR proteins. Calculated MW 93,2 kDa, SDS-PAGE observed MW 130 kDa. Potential sites of human BCAR1 phosphorylation (PhosphoSitePlus): tyrosine residues aa 12, 128, 165, 192, 222, 224, 234, 249, 267, 287, 306, 327, 362, 372, 387, 410, 653, 664, 666; serine residues aa 134, 139, 292, 437, 639; and threonine residues aa 269, 326, 385. Inducers of BCAR1 phosphorylation include cell matrix adhesion, extracellular matrix rigidity, growth factors, hormones and progression through the cell cycle. Phosphorylation of BCAR1 regulates BCAR1 dependent activities through altering protein interactions, protein localization and signaling cascades (Tikhmyanova et al., 2010).

Atlas Image
Figure 2. Schematic diagram containing BCAR1 protein domains.


BCAR1 domains as described in Tikhmyanova et al., 2010 are shown in the schematic diagram in figure 2. The amino terminal 1-65 aa contain the Src homology 3 domain (SH3) domain that binds proline-rich PxxP ligands. The adjacent region 66-447 aa contains the substrate domain (SD) comprised of 15 YxxP motifs that when phosphorylated by tyrosine kinases provides canonical binding sites for proteins containing SH2 domains such as Crk, mechanical forces and stretching of SD may induce conformational changes that allows phosphorylation by kinases and this stretching may promote protein-protein interactions in this domain (Sawada et al., 2006). The serine rich domain within 448-610 aa (serine rich protein interaction domain) contains a four-helix bundle that functions as a scaffold for BCAR1 binding proteins such as Grb2 and 14-3-3 (Nasertorabi et al., 2004; Briknarová et al., 2005). The C-terminal domain of 746-870 aa has a potential FAT (focal adhesion targeting) domain and a helix-loop-helix domain with homology to the transcription factor Id. This region contains the YDYVHL motif that is phosphorylated during cell adhesion.

BCAR1 interacting proteins (BioGRID)
CRKII, p60-Src, PTPN12, PTK2 (FAK), RapGEF1 (C3G), NPHP1, PTPN1 (PTP1B), FES, SHIP2 (INPPL1), ARHGAP32 (p250GAP), Pyk2 (PTK2B), Fyn, CRKL, YWHAZ, SrcIN1 (SNIP), p85-alpha (PI3KR1), c-ABL (bcr/abl), Lyn, Grb2, Dock1, paxillin, TRIP6, SH-PTP2, ID2A, UHRF2, NEDD9, NCK1, VCL, SAP1, Zyxin, BCAR3 (AND-34), CD2AP, LCK, SFN, SH2D3C, JNK/SAPK1, SH3KBP1, tensin 1 (TNS1), HCK, EFS, E2F2, VPS11, HspA5, TUBA1A, GADD34, p140Cap, BCAR1 (p130CAS), PTP-PEST, CIZ, Aurora-A, 14-3-3, CHAT-H, AIP4, APC/C and CDH1.


BCAR1 is ubiquitously expressed and is reportedly detectable in all phases of the cell cycle. In lymphoid development, BCAR is expressed at higher levels in differentiated cells compared to precursors. Barretts esophagus cancer cell line compared to normal tissue 2,51 increase in BCAR1 expression (Oncomine). Colorectal cancer Ramaswamy multi-cancer there is a 4,2 fold increase in BCAR1 expression compared to other cancers (Oncomine). Gastric cancer cell line Gyorffy cell line 2 there is a 5,0 fold reduction in BCAR 1 expression (Oncomine). In lymphomas, BCAR1 expression is reduced 2,5 fold (Oncomine).


Cytoplasm, ruffles, cell junctions (Donaldson et al., 2000), nucleus (Kim et al., 2004) and focal adhesions (Nakamoto et al., 1997; Volberg et al., 1995; Winograd-Katz et al., 2009).


BCAR1 regulates numerous cellular processes such as invasion, migration, transformation, survival and drug resistance (Di Stefano et al., 2011; Brábek et al., 2004; Brábek et al., 2005) (summarized in figure 3). BCAR1 lacks intrinsic enzymatic activity, yet it is a substrate for several kinases including the Src tyrosine kinase. The original name for BCAR1 was p130CAS abbreviated from Crk-associated substrate because it was first identified as a tyrosine phosphorylated protein in cells transformed by v-src and v-crk oncogenes. BCAR1 regulates cellular behavior by controlling signaling cascades and the dynamic localization of multi-protein complexes. The BCAR1 phosphorylation state is regulated during the cell cycle. During the exit of G2, BCAR1 serine and threonine phosphorylation levels increase and these events disrupt the interactions of BCAR1 with Src and FAK and thus dissociates this complex and contributes to the disassembly of focal adhesions allowing cells to loosen matrix adhesions and thus permitting cell rounding in mitosis. The subsequent reformation of matrix adhesions promotes progression through the cell cycle from mitosis to G1 (Pugacheva et al., 2006).
Atlas Image
Figure 3. Extracellular cues that control CAR1 phosphorylation and cellular processes that are regulated by BCAR1.


There is a family containing four proteins related to BCAR1 (breast cancer resistance) that possess names related to the prior nomenclature for BCAR1 homologs in the rat and mouse. The non-human homologs of BCAR1 were named CAS for Crk-associated substrate. This family of proteins includes the protein EFS (embryonal Fyn-associated substrate) (CAS3, CASS3, EFS1, EFS2, HEFS, SIN) identified because of interactions with the Src-family kinases Fyn and Yes and maps to chromosome 14q11.2-q12. A third family member is HEF1 (human enhancer of filamentation 1 known as CASL, CAS-L, NEDD9, CAS2 and CASS2) that maps to chromosome 6p25-p24 and was isolated as a human gene that promotes filamentous growth in yeast. This screen was performed to identify regulators of the cell cycle and polarity. It was also identified as a protein that is tyrosine phosphorylated after clustering integrin β1 in T-lymphocytes. NEDD9 (neural precursor cell expressed, developmentally down-regulated 9) is a gene restricted in expression to early embryonic, but not adult mouse brain. The fourth family member is CASS4 ((HEF-EFS-P130CAS-like)/CAS4) that maps to chromosome 20q13.2-q13.31 and is the newest member of the family that was identified by genomic and transcript homology and demonstrated to function similarly to other BCAR family members. These 4 proteins are conserved from jawed vertebrates through mammals. One BCAR member is found in lower vertebrates and insects. However, no BCAR family member is detectable in C. elegans, S. cerevisiae and other lower eukaryotes.



Catalogue of somatic mutations in cancer: there are currently 10 known somatic mutations in BCAR1. Proceeding from the N-terminus to the C-Terminus of BCAR1, aa 118 proline (identified in the central nervous system), 185 alanine (identified in the central nervous system), 407 threonine (identified in breast tissue), 430 serine (upper aerodigestive tract), 583 serine (identified in prostate tissue), 592 histidine (identified in liver), 708 lysine (identified in the central nervous system), 759 threonine (identified in central nervous system), 780 valine (identified in central nervous system), 795 isoleucine (identified in upper aerodigestive tract). Mutations at aa 118 and 185 are in the substrate domain, 407 and 430 are amino-terminal to the 4 helical bundle, 583 and 592 are in the 4-helix bundle, whereas 759, 780 and 795 localize to the C-terminal domain.

Implicated in

Entity name
Various cancers
Overexpression of BCAR1 is linked to poor prognosis and increased cancer metastasis in many cancers. BCAR1 can be upregulated by gene amplification, transcriptional upregulation and changes in protein stability. Hyperphosphorylation of BCAR1 drives cell migration, invasion, cell survival and drug resistance.
Entity name
Breast cancer
In breast cancers that express high levels of BCAR1, the cancer is more likely to relapse and the tumors frequently have an intrinsic reduced response to tamoxifen (van der Flier et al., 2000; Dorssers et al., 2004).
Elevated BCAR levels in breast cancers correlates with increased expression of HER2/neu and enhanced cell proliferation (Cabodi et al., 2006; Cabodi et al., 2010). BCAR1 overexpression in breast cancer cells is linked to resistance to the cytotoxic agent Adriamycin (Ta et al., 2008). BCAR1 overexpression is sufficient to induce hyperplasia in the mammary pad during development and pregnancy.
Entity name
Prostate cancer
In prostate cancer, BCAR1 expression is higher compared to control tissue and expression of BCAR1 in prostate cancer correlates with elevated EGFR expression levels (Fromont et al., 2007; Fromont et al., 2011; Cabodi et al., 2010).
Entity name
Hepatocellular carcinoma
In hepatocellular carcinoma, tumor invasion and poor prognosis correlate with overexpression of BCAR1 and reductions in E-cadherin and β-catenin levels (Guo et al., 2008).
Entity name
Nasal polyps
Nasal polyps can express high levels of BCAR1 (Zhang et al., 2003).
Entity name
Colorectal cancer
Celecoxib cytotoxicity in colorectal cancer is linked to cleavage of BCAR1 and apoptosis. Overexpression of BCAR1 in colorectal cancer cell lines is linked to resistance to celecoxib (Casanova et al., 2006; Weyant et al., 2000).
Entity name
Non-small-cell lung cancer (NSCLC)
BCAR1 is not detected in normal lung tissue, however in non-small-cell lung cancer and tuberculosis and other pulmonary disorders elevated levels of BCAR1 are observed in both the diseased tissue and elevated levels are noted in serum (Deng et al., 2011). In patients with NSCLC the serum levels of BCAR1 proportionally increase with the progression of tumor stage. Interestingly, in patients with elevated serum BCAR1 levels, the serum levels of BCAR1 diminish after removal of the pulmonary lesion or tumor.
Entity name
Ovarian cancer
In ovarian cancer, an increase in BCAR1 expression correlates with poor 5 year survival rates and reductions in BCAR1 expression result in reduced tumor growth following docetaxel chemotherapy (Nick et al., 2011).
Entity name
Oral cancer
In oral cancers elevated levels of UPAR are indicative of more invasive tumors and enhanced lymph node metastasis. The levels of UPAR in oral cancer correlate with the levels of BCAR1 (Shi et al., 2011).
In anaplastic large-cell lymphomas, the anaplastic lymphoma kinase (ALK) is frequently translocated and a fusion protein with nucleophosmin (NPM)-ALK is generated that contains kinase activity. NPM-ALK transforms fibroblasts, however in BCAR1-/- fibroblasts NPM-ALK fails to induce transformation. Hence, BCAR1 is critical for ALK transformation activity (Ambrogio et al., 2005).
Entity name
Chemotherapeutic resistance
Overexpression of BCAR1 is linked to drug resistance in multiple tumor types such as breast cancer, lung cancers, glioblastoma and melanoma (Ta et al., 2008). BCAR1 and NEDD9 interact with BCAR3 to mediate anti-estrogen resistance and to control Rap1 GTPase activation (Cai et al., 2003). In a screen of an estrogen dependent cell line, BCAR1 was identified as a gene required for tamoxifen resistance (Brinkman et al., 2000; van der Flier et al., 2000).
Entity name
Role of BCAR1 in other pathological conditions or diseases
BCAR1 dysfunction is linked to inflammatory disorders, ischemic stroke (Ziemka-Nalecz et al., 2007; Zalewska et al., 2005) and developmental defects. Knockout of BCAR1 is lethal at embryonic stages days 11,5 to 12,5 as a result of cardiovascular dysfunction (Honda et al., 1998). BCAR1 is critical for the pathology of many infectious diseases. The bacterial species Yersinia encodes and secretes a phosphatase YOP that inactivates/dephosphorylates BCAR1 and YOP activity minimizes phagocytosis by macrophages and neutrophils facilitating Yersinia evasion of components of the cellular immune response which disrupts clearance of the bacteria by the host (Deleuil et al., 2003; Hamid et al., 1999). In contrast, in epithelial cells, Yersinia uptake is associated with phosphorylation of BCAR1, thus the bacterium triggers BCAR1 phosphorylation to promote the uptake of the organism in non-phagocytic cells (Weidow et al., 2000). S. typhimurium is an obligate intracellular bacterial pathogen that requires eukaryotic cellular uptake for infection. These bacteria utilize host eukaryotic BCAR1 for efficient bacterial uptake and their infectious cycle (Shi et al., 2006). In addition to bacteria, many viruses also utilize the host protein machinery and BCAR1 for their viral propagation. For instance, internalization of adenovirus is initiated by virus binding to host integrin receptors and virus internalization requires BCAR1 phosphorylation (Li et al., 1998; Li et al., 2000).


Pubmed IDLast YearTitleAuthors
161059842005p130Cas mediates the transforming properties of the anaplastic lymphoma kinase.Ambrogio C et al
89952521997The related adhesion focal tyrosine kinase is tyrosine-phosphorylated after beta1-integrin stimulation in B cells and binds to p130cas.Astier A et al
181981292008Tac-beta1 inhibits FAK activation and Src signaling.Berrier AL et al
159728492005Crk-associated substrate tyrosine phosphorylation sites are critical for invasion and metastasis of SRC-transformed cells.Brábek J et al
157952252005The serine-rich domain from Crk-associated substrate (p130cas) is a four-helix bundle.Briknarová K et al
106395122000BCAR1, a human homologue of the adapter protein p130Cas, and antiestrogen resistance in breast cancer cells.Brinkman A et al
86497891996The identification of p130cas-binding proteins and their role in cellular transformation.Burnham MR et al
205051162010p130Cas is an essential transducer element in ErbB2 transformation.Cabodi S et al
211026362010Integrin signalling adaptors: not only figurants in the cancer story.Cabodi S et al
145834772003AND-34/BCAR3, a GDP exchange factor whose overexpression confers antiestrogen resistance, activates Rac, PAK1, and the cyclin D1 promoter.Cai D et al
163531452006Celecoxib induces anoikis in human colon carcinoma cells associated with the deregulation of focal adhesions and nuclear translocation of p130Cas.Casanova I et al
125424702003Interaction between the Yersinia protein tyrosine phosphatase YopH and eukaryotic Cas/Fyb is an important virulence mechanism.Deleuil F et al
214697682011Breast cancer anti-estrogen resistance protein 1 (BCAR1/p130cas) in pulmonary disease tissue and serum.Deng B et al
219949042011The adaptor proteins p140CAP and p130CAS as molecular hubs in cell migration and invasion of cancer cells.Di Stefano P et al
107396642000Crk-associated substrate p130(Cas) interacts with nephrocystin and both proteins localize to cell-cell contacts of polarized epithelial cells.Donaldson JC et al
154480072004The prognostic value of BCAR1 in patients with primary breast cancer.Dorssers LC et al
217205502011Carcinoma matrix controls resistance to cisplatin through talin regulation of NF-kB.Eberle KE et al
213467852011The integrin signalling adaptor p130CAS is also a key player in prostate cancer.Fromont G et al
171928742007BCAR1 expression in prostate cancer: association with 16q23 LOH status, tumor progression and EGFR/KAI1 staining.Fromont G et al
108969382000p130Cas regulates the activity of AND-34, a novel Ral, Rap1, and R-Ras guanine nucleotide exchange factor.Gotoh T et al
188424952008Relation among p130Cas, E-cadherin and beta-catenin expression, clinicopathologic significance and prognosis in human hepatocellular carcinoma.Guo C et al
105024641999YopH dephosphorylates Cas and Fyn-binding protein in macrophages.Hamid N et al
86629211996p130Cas, a substrate associated with v-Src and v-Crk, localizes to focal adhesions and binds to focal adhesion kinase.Harte MT et al
96976971998Cardiovascular anomaly, impaired actin bundling and resistance to Src-induced transformation in mice lacking p130Cas.Honda H et al
87005071996Networks of interaction of p120cbl and p130cas with Crk and Grb2 adaptor proteins.Khwaja A et al
146606142004The 31-kDa caspase-generated cleavage product of p130cas functions as a transcriptional repressor of E2A in apoptotic cells.Kim W et al
94720461998CAS/Crk coupling serves as a "molecular switch" for induction of cell migration.Klemke RL et al
107995622000Association of p130CAS with phosphatidylinositol-3-OH kinase mediates adenovirus cell entry.Li E et al
106697422000CIZ, a zinc finger protein that interacts with p130(cas) and activates the expression of matrix metalloproteinases.Nakamoto T et al
154856522004Organization of functional domains in the docking protein p130Cas.Nasertorabi F et al
219572302011Silencing of p130cas in ovarian carcinoma: a novel mechanism for tumor cell death.Nick AM et al
169194362006Interdependence of cell attachment and cell cycle signaling.Pugacheva EN et al
80704031994A novel signaling molecule, p130, forms stable complexes in vivo with v-Crk and v-Src in a tyrosine phosphorylation-dependent manner.Sakai R et al
212918602011Integrin αβ1, αvβ, α6β effectors p130Cas, Src and talin regulate carcinoma invasion and chemoresistance.Sansing HA et al
171297852006Force sensing by mechanical extension of the Src family kinase substrate p130Cas.Sawada Y et al
169145152006Invasion of host cells by Salmonella typhimurium requires focal adhesion kinase and p130Cas.Shi J et al
216300912011Urinary-type plasminogen activator receptor (uPAR) modulates oral cancer cell behavior with alteration in p130cas.Shi Z et al
189741222008A novel association between p130Cas and resistance to the chemotherapeutic drug adriamycin in human breast cancer cells.Ta HQ et al
217659372011NEDD9 and BCAR1 negatively regulate E-cadherin membrane localization, and promote E-cadherin degradation.Tikhmyanova N et al
179826772007Activation of the FAK-src molecular scaffolds and p130Cas-JNK signaling cascades by alpha1-integrins during colon cancer cell invasion.Van Slambrouck S et al
76733451995Focal adhesion formation by F9 embryonal carcinoma cells after vinculin gene disruption.Volberg T et al
86493681996Introduction of p130cas signaling complex formation upon integrin-mediated cell adhesion: a role for Src family kinases.Vuori K et al
75456761995Tyrosine phosphorylation of p130Cas and cortactin accompanies integrin-mediated cell adhesion to extracellular matrix.Vuori K et al
112076072000CAS/Crk signalling mediates uptake of Yersinia into human epithelial cells.Weidow CL et al
107417202000Colon cancer chemopreventive drugs modulate integrin-mediated signaling pathways.Weyant MJ et al
196671302009Multiparametric analysis of focal adhesion formation by RNAi-mediated gene knockdown.Winograd-Katz SE et al
117824562002Members of the Zyxin family of LIM proteins interact with members of the p130Cas family of signal transducers.Yi J et al
160958662005Neonatal cerebral hypoxia-ischemia: involvement of FAK-dependent pathway.Zalewska T et al
145677192003Growth factors and receptors in juvenile nasopharyngeal angiofibroma and nasal polyps: an immunohistochemical study.Zhang PJ et al
220348752011The docking protein p130Cas regulates cell sensitivity to proteasome inhibition.Zhao M et al
175245232007Transient forebrain ischemia effects FAK-coupled signaling in gerbil hippocampus.Ziemka-Nałecz M et al
106395132000Bcar1/p130Cas protein and primary breast cancer: prognosis and response to tamoxifen treatment.van der Flier S et al

Other Information

Locus ID:

NCBI: 9564
MIM: 602941
HGNC: 971
Ensembl: ENSG00000050820


dbSNP: 9564
ClinVar: 9564
TCGA: ENSG00000050820


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Focal adhesionKEGGko04510
Leukocyte transendothelial migrationKEGGko04670
Regulation of actin cytoskeletonKEGGko04810
Focal adhesionKEGGhsa04510
Leukocyte transendothelial migrationKEGGhsa04670
Regulation of actin cytoskeletonKEGGhsa04810
Chemokine signaling pathwayKEGGko04062
Chemokine signaling pathwayKEGGhsa04062
Bacterial invasion of epithelial cellsKEGGko05100
Bacterial invasion of epithelial cellsKEGGhsa05100
Rap1 signaling pathwayKEGGhsa04015
Rap1 signaling pathwayKEGGko04015
Platelet activation, signaling and aggregationREACTOMER-HSA-76002
Platelet Aggregation (Plug Formation)REACTOMER-HSA-76009
Integrin alphaIIb beta3 signalingREACTOMER-HSA-354192
p130Cas linkage to MAPK signaling for integrinsREACTOMER-HSA-372708
Signal TransductionREACTOMER-HSA-162582
Signaling by PDGFREACTOMER-HSA-186797
Downstream signal transductionREACTOMER-HSA-186763
Signaling by VEGFREACTOMER-HSA-194138
Signaling by PTK6REACTOMER-HSA-8848021
PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinasesREACTOMER-HSA-8849471

Protein levels (Protein atlas)

Not detected


Entity IDNameTypeEvidenceAssociationPKPDPMIDs


Pubmed IDYearTitleCitations
171297852006Force sensing by mechanical extension of the Src family kinase substrate p130Cas.353
187255412008uPAR promotes formation of the p130Cas-Crk complex to activate Rac through DOCK180.55
212453812011Neuropilin-1 signaling through p130Cas tyrosine phosphorylation is essential for growth factor-dependent migration of glioma and endothelial cells.51
213063012011Neuropilin-1 mediates PDGF stimulation of vascular smooth muscle cell migration and signalling via p130Cas.51
117797092002Tyrosine phosphorylation of paxillin, FAK, and p130CAS: effects on cell spreading and migration.48
165977012006Fibronectin rigidity response through Fyn and p130Cas recruitment to the leading edge.48
223956102012Dimensional and temporal controls of three-dimensional cell migration by zyxin and binding partners.45
160408042005Ganglioside GD3 promotes cell growth and invasion through p130Cas and paxillin in malignant melanoma cells.43
198225232009p130Cas is required for mammary tumor growth and transforming growth factor-beta-mediated metastasis through regulation of Smad2/3 activity.40
190290902009The lysyl oxidase pro-peptide attenuates fibronectin-mediated activation of focal adhesion kinase and p130Cas in breast cancer cells.37


Allison Berrier

BCAR1 (breast cancer anti-estrogen resistance 1)

Atlas Genet Cytogenet Oncol Haematol. 2011-12-01

Online version: http://atlasgeneticsoncology.org/gene/761/bcar1-(breast-cancer-anti-estrogen-resistance-1)