Note | 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). |
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| Figure 2. Schematic diagram containing BCAR1 protein domains. |
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Description | 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. |
Expression | 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. Barrett's 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). |
Localisation | 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). |
Function | 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). |
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| Figure 3. Extracellular cues that control CAR1 phosphorylation and cellular processes that are regulated by BCAR1. |
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Homology | 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. |
p130Cas mediates the transforming properties of the anaplastic lymphoma kinase. |
Ambrogio C, Voena C, Manazza AD, Piva R, Riera L, Barberis L, Costa C, Tarone G, Defilippi P, Hirsch E, Boeri Erba E, Mohammed S, Jensen ON, Palestro G, Inghirami G, Chiarle R. |
Blood. 2005 Dec 1;106(12):3907-16. Epub 2005 Aug 16. |
PMID 16105984 |
|
The related adhesion focal tyrosine kinase is tyrosine-phosphorylated after beta1-integrin stimulation in B cells and binds to p130cas. |
Astier A, Avraham H, Manie SN, Groopman J, Canty T, Avraham S, Freedman AS. |
J Biol Chem. 1997 Jan 3;272(1):228-32. |
PMID 8995252 |
|
Tac-beta1 inhibits FAK activation and Src signaling. |
Berrier AL, Jones CW, LaFlamme SE. |
Biochem Biophys Res Commun. 2008 Mar 28;368(1):62-7. Epub 2008 Jan 14. |
PMID 18198129 |
|
Crk-associated substrate tyrosine phosphorylation sites are critical for invasion and metastasis of SRC-transformed cells. |
Brabek J, Constancio SS, Siesser PF, Shin NY, Pozzi A, Hanks SK. |
Mol Cancer Res. 2005 Jun;3(6):307-15. |
PMID 15972849 |
|
The serine-rich domain from Crk-associated substrate (p130cas) is a four-helix bundle. |
Briknarova K, Nasertorabi F, Havert ML, Eggleston E, Hoyt DW, Li C, Olson AJ, Vuori K, Ely KR. |
J Biol Chem. 2005 Jun 10;280(23):21908-14. Epub 2005 Mar 28. |
PMID 15795225 |
|
BCAR1, a human homologue of the adapter protein p130Cas, and antiestrogen resistance in breast cancer cells. |
Brinkman A, van der Flier S, Kok EM, Dorssers LC. |
J Natl Cancer Inst. 2000 Jan 19;92(2):112-20. |
PMID 10639512 |
|
The identification of p130cas-binding proteins and their role in cellular transformation. |
Burnham MR, Harte MT, Richardson A, Parsons JT, Bouton AH. |
Oncogene. 1996 Jun 6;12(11):2467-72. |
PMID 8649789 |
|
p130Cas is an essential transducer element in ErbB2 transformation. |
Cabodi S, Tinnirello A, Bisaro B, Tornillo G, del Pilar Camacho-Leal M, Forni G, Cojoca R, Iezzi M, Amici A, Montani M, Eva A, Di Stefano P, Muthuswamy SK, Tarone G, Turco E, Defilippi P. |
FASEB J. 2010 Oct;24(10):3796-808. Epub 2010 May 26. |
PMID 20505116 |
|
Integrin signalling adaptors: not only figurants in the cancer story. |
Cabodi S, del Pilar Camacho-Leal M, Di Stefano P, Defilippi P. |
Nat Rev Cancer. 2010 Dec;10(12):858-70. Epub 2010 Nov 24. (REVIEW) |
PMID 21102636 |
|
AND-34/BCAR3, a GDP exchange factor whose overexpression confers antiestrogen resistance, activates Rac, PAK1, and the cyclin D1 promoter. |
Cai D, Iyer A, Felekkis KN, Near RI, Luo Z, Chernoff J, Albanese C, Pestell RG, Lerner A. |
Cancer Res. 2003 Oct 15;63(20):6802-8. |
PMID 14583477 |
|
Celecoxib induces anoikis in human colon carcinoma cells associated with the deregulation of focal adhesions and nuclear translocation of p130Cas. |
Casanova I, Parreno M, Farre L, Guerrero S, Cespedes MV, Pavon MA, Sancho FJ, Marcuello E, Trias M, Mangues R. |
Int J Cancer. 2006 May 15;118(10):2381-9. |
PMID 16353145 |
|
Interaction between the Yersinia protein tyrosine phosphatase YopH and eukaryotic Cas/Fyb is an important virulence mechanism. |
Deleuil F, Mogemark L, Francis MS, Wolf-Watz H, Fallman M. |
Cell Microbiol. 2003 Jan;5(1):53-64. |
PMID 12542470 |
|
Breast cancer anti-estrogen resistance protein 1 (BCAR1/p130cas) in pulmonary disease tissue and serum. |
Deng B, Huang W, Tan QY, Fan XQ, Jiang YG, Liu L, Zhong YY, Liang YG, Wang RW. |
Mol Diagn Ther. 2011 Feb 1;15(1):31-40. doi: 10.2165/11588850-000000000-00000. |
PMID 21469768 |
|
The adaptor proteins p140CAP and p130CAS as molecular hubs in cell migration and invasion of cancer cells. |
Di Stefano P, Leal MP, Tornillo G, Bisaro B, Repetto D, Pincini A, Santopietro E, Sharma N, Turco E, Cabodi S, Defilippi P. |
Am J Cancer Res. 2011;1(5):663-73. Epub 2011 May 2. |
PMID 21994904 |
|
Crk-associated substrate p130(Cas) interacts with nephrocystin and both proteins localize to cell-cell contacts of polarized epithelial cells. |
Donaldson JC, Dempsey PJ, Reddy S, Bouton AH, Coffey RJ, Hanks SK. |
Exp Cell Res. 2000 Apr 10;256(1):168-78. |
PMID 10739664 |
|
The prognostic value of BCAR1 in patients with primary breast cancer. |
Dorssers LC, Grebenchtchikov N, Brinkman A, Look MP, van Broekhoven SP, de Jong D, Peters HA, Portengen H, Meijer-van Gelder ME, Klijn JG, van Tienoven DT, Geurts-Moespot A, Span PN, Foekens JA, Sweep FC. |
Clin Cancer Res. 2004 Sep 15;10(18 Pt 1):6194-202. |
PMID 15448007 |
|
Carcinoma matrix controls resistance to cisplatin through talin regulation of NF-kB. |
Eberle KE, Sansing HA, Szaniszlo P, Resto VA, Berrier AL. |
PLoS One. 2011;6(6):e21496. Epub 2011 Jun 24. |
PMID 21720550 |
|
The integrin signalling adaptor p130CAS is also a key player in prostate cancer. |
Fromont G, Cussenot O. |
Nat Rev Cancer. 2011 Mar;11(3):227. |
PMID 21346785 |
|
BCAR1 expression in prostate cancer: association with 16q23 LOH status, tumor progression and EGFR/KAI1 staining. |
Fromont G, Vallancien G, Validire P, Levillain P, Cussenot O. |
Prostate. 2007 Feb 15;67(3):268-73. |
PMID 17192874 |
|
p130Cas regulates the activity of AND-34, a novel Ral, Rap1, and R-Ras guanine nucleotide exchange factor. |
Gotoh T, Cai D, Tian X, Feig LA, Lerner A. |
J Biol Chem. 2000 Sep 29;275(39):30118-23. |
PMID 10896938 |
|
Relation among p130Cas, E-cadherin and beta-catenin expression, clinicopathologic significance and prognosis in human hepatocellular carcinoma. |
Guo C, Liu QG, Yang W, Zhang ZL, Yao YM. |
Hepatobiliary Pancreat Dis Int. 2008 Oct;7(5):490-6. |
PMID 18842495 |
|
YopH dephosphorylates Cas and Fyn-binding protein in macrophages. |
Hamid N, Gustavsson A, Andersson K, McGee K, Persson C, Rudd CE, Fallman M. |
Microb Pathog. 1999 Oct;27(4):231-42. |
PMID 10502464 |
|
p130Cas. |
Hanks SK, Brabek J. |
UCSD Nature Molecule Pages. 2005 Oct 10; Protein A001708. |
|
p130Cas, a substrate associated with v-Src and v-Crk, localizes to focal adhesions and binds to focal adhesion kinase. |
Harte MT, Hildebrand JD, Burnham MR, Bouton AH, Parsons JT. |
J Biol Chem. 1996 Jun 7;271(23):13649-55. |
PMID 8662921 |
|
Cardiovascular anomaly, impaired actin bundling and resistance to Src-induced transformation in mice lacking p130Cas. |
Honda H, Oda H, Nakamoto T, Honda Z, Sakai R, Suzuki T, Saito T, Nakamura K, Nakao K, Ishikawa T, Katsuki M, Yazaki Y, Hirai H. |
Nat Genet. 1998 Aug;19(4):361-5. |
PMID 9697697 |
|
Networks of interaction of p120cbl and p130cas with Crk and Grb2 adaptor proteins. |
Khwaja A, Hallberg B, Warne PH, Downward J. |
Oncogene. 1996 Jun 20;12(12):2491-8. |
PMID 8700507 |
|
The 31-kDa caspase-generated cleavage product of p130cas functions as a transcriptional repressor of E2A in apoptotic cells. |
Kim W, Kook S, Kim DJ, Teodorof C, Song WK. |
J Biol Chem. 2004 Feb 27;279(9):8333-42. Epub 2003 Dec 2. |
PMID 14660614 |
|
CAS/Crk coupling serves as a "molecular switch" for induction of cell migration. |
Klemke RL, Leng J, Molander R, Brooks PC, Vuori K, Cheresh DA. |
J Cell Biol. 1998 Feb 23;140(4):961-72. |
PMID 9472046 |
|
Association of p130CAS with phosphatidylinositol-3-OH kinase mediates adenovirus cell entry. |
Li E, Stupack DG, Brown SL, Klemke R, Schlaepfer DD, Nemerow GR. |
J Biol Chem. 2000 May 12;275(19):14729-35. |
PMID 10799562 |
|
CIZ, a zinc finger protein that interacts with p130(cas) and activates the expression of matrix metalloproteinases. |
Nakamoto T, Yamagata T, Sakai R, Ogawa S, Honda H, Ueno H, Hirano N, Yazaki Y, Hirai H. |
Mol Cell Biol. 2000 Mar;20(5):1649-58. |
PMID 10669742 |
|
Organization of functional domains in the docking protein p130Cas. |
Nasertorabi F, Garcia-Guzman M, Briknarova K, Larsen E, Havert ML, Vuori K, Ely KR. |
Biochem Biophys Res Commun. 2004 Nov 19;324(3):993-8. |
PMID 15485652 |
|
Silencing of p130cas in ovarian carcinoma: a novel mechanism for tumor cell death. |
Nick AM, Stone RL, Armaiz-Pena G, Ozpolat B, Tekedereli I, Graybill WS, Landen CN, Villares G, Vivas-Mejia P, Bottsford-Miller J, Kim HS, Lee JS, Kim SM, Baggerly KA, Ram PT, Deavers MT, Coleman RL, Lopez-Berestein G, Sood AK. |
J Natl Cancer Inst. 2011 Nov 2;103(21):1596-612. Epub 2011 Sep 28. |
PMID 21957230 |
|
Interdependence of cell attachment and cell cycle signaling. |
Pugacheva EN, Roegiers F, Golemis EA. |
Curr Opin Cell Biol. 2006 Oct;18(5):507-15. Epub 2006 Aug 17. (REVIEW) |
PMID 16919436 |
|
A novel signaling molecule, p130, forms stable complexes in vivo with v-Crk and v-Src in a tyrosine phosphorylation-dependent manner. |
Sakai R, Iwamatsu A, Hirano N, Ogawa S, Tanaka T, Mano H, Yazaki Y, Hirai H. |
EMBO J. 1994 Aug 15;13(16):3748-56. |
PMID 8070403 |
|
Integrin alphabeta1, alphavbeta, alpha6beta effectors p130Cas, Src and talin regulate carcinoma invasion and chemoresistance. |
Sansing HA, Sarkeshik A, Yates JR, Patel V, Gutkind JS, Yamada KM, Berrier AL. |
Biochem Biophys Res Commun. 2011 Mar 11;406(2):171-6. Epub 2011 Feb 1. |
PMID 21291860 |
|
Force sensing by mechanical extension of the Src family kinase substrate p130Cas. |
Sawada Y, Tamada M, Dubin-Thaler BJ, Cherniavskaya O, Sakai R, Tanaka S, Sheetz MP. |
Cell. 2006 Dec 1;127(5):1015-26. |
PMID 17129785 |
|
Invasion of host cells by Salmonella typhimurium requires focal adhesion kinase and p130Cas. |
Shi J, Casanova JE. |
Mol Biol Cell. 2006 Nov;17(11):4698-708. Epub 2006 Aug 16. |
PMID 16914515 |
|
Urinary-type plasminogen activator receptor (uPAR) modulates oral cancer cell behavior with alteration in p130cas. |
Shi Z, Liu Y, Johnson JJ, Stack MS. |
Mol Cell Biochem. 2011 Nov;357(1-2):151-61. Epub 2011 Jun 1. |
PMID 21630091 |
|
A novel association between p130Cas and resistance to the chemotherapeutic drug adriamycin in human breast cancer cells. |
Ta HQ, Thomas KS, Schrecengost RS, Bouton AH. |
Cancer Res. 2008 Nov 1;68(21):8796-804. |
PMID 18974122 |
|
NEDD9 and BCAR1 negatively regulate E-cadherin membrane localization, and promote E-cadherin degradation. |
Tikhmyanova N, Golemis EA. |
PLoS One. 2011;6(7):e22102. Epub 2011 Jul 12. |
PMID 21765937 |
|
Activation of the FAK-src molecular scaffolds and p130Cas-JNK signaling cascades by alpha1-integrins during colon cancer cell invasion. |
Van Slambrouck S, Grijelmo C, De Wever O, Bruyneel E, Emami S, Gespach C, Steelant WF. |
Int J Oncol. 2007 Dec;31(6):1501-8. |
PMID 17982677 |
|
Focal adhesion formation by F9 embryonal carcinoma cells after vinculin gene disruption. |
Volberg T, Geiger B, Kam Z, Pankov R, Simcha I, Sabanay H, Coll JL, Adamson E, Ben-Ze'ev A. |
J Cell Sci. 1995 Jun;108 ( Pt 6):2253-60. |
PMID 7673345 |
|
Introduction of p130cas signaling complex formation upon integrin-mediated cell adhesion: a role for Src family kinases. |
Vuori K, Hirai H, Aizawa S, Ruoslahti E. |
Mol Cell Biol. 1996 Jun;16(6):2606-13. |
PMID 8649368 |
|
Tyrosine phosphorylation of p130Cas and cortactin accompanies integrin-mediated cell adhesion to extracellular matrix. |
Vuori K, Ruoslahti E. |
J Biol Chem. 1995 Sep 22;270(38):22259-62. |
PMID 7545676 |
|
CAS/Crk signalling mediates uptake of Yersinia into human epithelial cells. |
Weidow CL, Black DS, Bliska JB, Bouton AH. |
Cell Microbiol. 2000 Dec;2(6):549-60. |
PMID 11207607 |
|
Colon cancer chemopreventive drugs modulate integrin-mediated signaling pathways. |
Weyant MJ, Carothers AM, Bertagnolli ME, Bertagnolli MM. |
Clin Cancer Res. 2000 Mar;6(3):949-56. |
PMID 10741720 |
|
Multiparametric analysis of focal adhesion formation by RNAi-mediated gene knockdown. |
Winograd-Katz SE, Itzkovitz S, Kam Z, Geiger B. |
J Cell Biol. 2009 Aug 10;186(3):423-36. |
PMID 19667130 |
|
Members of the Zyxin family of LIM proteins interact with members of the p130Cas family of signal transducers. |
Yi J, Kloeker S, Jensen CC, Bockholt S, Honda H, Hirai H, Beckerle MC. |
J Biol Chem. 2002 Mar 15;277(11):9580-9. Epub 2002 Jan 8. |
PMID 11782456 |
|
Neonatal cerebral hypoxia-ischemia: involvement of FAK-dependent pathway. |
Zalewska T, Makarewicz D, Janik B, Ziemka-Nalecz M. |
Int J Dev Neurosci. 2005 Nov;23(7):657-62. Epub 2005 Aug 10. |
PMID 16095866 |
|
Growth factors and receptors in juvenile nasopharyngeal angiofibroma and nasal polyps: an immunohistochemical study. |
Zhang PJ, Weber R, Liang HH, Pasha TL, LiVolsi VA. |
Arch Pathol Lab Med. 2003 Nov;127(11):1480-4. |
PMID 14567719 |
|
The docking protein p130Cas regulates cell sensitivity to proteasome inhibition. |
Zhao M, Vuori K. |
BMC Biol. 2011 Oct 28;9:73. |
PMID 22034875 |
|
Transient forebrain ischemia effects FAK-coupled signaling in gerbil hippocampus. |
Ziemka-Nalecz M, Zalewska T. |
Neurochem Int. 2007 Nov-Dec;51(6-7):405-11. Epub 2007 Apr 22. |
PMID 17524523 |
|
Bcar1/p130Cas protein and primary breast cancer: prognosis and response to tamoxifen treatment. |
van der Flier S, Brinkman A, Look MP, Kok EM, Meijer-van Gelder ME, Klijn JG, Dorssers LC, Foekens JA. |
J Natl Cancer Inst. 2000 Jan 19;92(2):120-7. |
PMID 10639513 |
|