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Gene Review

BCAR1  -  breast cancer anti-estrogen resistance 1

Homo sapiens

Synonyms: Breast cancer anti-estrogen resistance protein 1, CAS, CAS1, CASS1, CRK-associated substrate, ...
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Disease relevance of BCAR1


Psychiatry related information on BCAR1


High impact information on BCAR1

  • METHODS/RESULTS: Transfer of the BCAR1 locus from retrovirus-mutated, antiestrogen-resistant cells to estrogen-dependent ZR-75-1 cells by cell fusion conferred an antiestrogen-resistant phenotype on the recipient cells [1].
  • Genomic analysis revealed that BCAR1 consists of seven exons and is located at chromosome 16q23 [1].
  • Transfection of BCAR1 cDNA into ZR-75-1 cells again resulted in sustained cell proliferation in the presence of antiestrogens, confirming that BCAR1 was the responsible gene in the locus [1].
  • The complete coding sequence of BCAR1 was isolated by use of exon-trapping and complementary DNA (cDNA) library screening [1].
  • In multivariate analysis for response, Bcar1/p130Cas was independent of classical predictive factors, such as estrogen receptor status, age/menopausal status, disease-free interval, and dominant site of relapse [8].

Chemical compound and disease context of BCAR1


Biological context of BCAR1

  • Here we show that stimulated MCSP recruits tyrosine-phosphorylated p130 cas, an adaptor protein important in tumour cell motility and invasion [4].
  • In contrast, Cas tyrosine phosphorylation was observed in certain B cell lines but not in tonsillar B cells, indicating a more general role for HEF1 in B cell signaling [12].
  • The Crk-associated substrate p130(Cas) (Cas) and the recently described human enhancer of filamentation 1 (HEF1) are two proteins with similar structure (64% amino acid homology), which are thought to act as "docking" molecules in intracellular signaling cascades [12].
  • BCAR1 expression was inversely correlated with 16q23 LOH status (P < 0.001), and was associated with high EGFR staining (P < 0.02), and negative KAI1 expression (P < 0.01) [13].
  • Sequence homology and structural compatibility suggest a FAT-like fold for the C-terminal domains of CAS, Efs/Sin, and HEF1 [14].

Anatomical context of BCAR1


Associations of BCAR1 with chemical compounds


Enzymatic interactions of BCAR1

  • Mutation of proline 337 within this sequence to alanine significantly impairs the ability of PTP-PEST to recognise tyrosine phosphorylated p130cas as a substrate, without qualitatively affecting the selectivity of the interaction [21].

Regulatory relationships of BCAR1


Other interactions of BCAR1

  • Phosphorylation of residues in the N-terminus of paxillin by these kinases permits the regulated recruitment of downstream effector molecules such as CRK, which (via association with CAS) is important for transduction of external signals into changes in cell motility and for modulation of gene expression by the various MAP kinase cascades [26].
  • Crk associated substrate (Cas), Nck, and focal adhesion kinase (FAK) were also phosphorylated after SDF-1alpha stimulation [27].
  • Involvement of p130(Cas) and p105(HEF1), a novel Cas-like docking protein, in a cytoskeleton-dependent signaling pathway initiated by ligation of integrin or antigen receptor on human B cells [12].
  • CONCLUSIONS: The quantitative BCAR1 protein level represents a prognostic factor for RFS and OS in primary breast cancer, independent of the traditional prognostic factors and the other novel marker PAI-1 [16].
  • METHODS: We have measured the expression changes induced by overexpression of the BCAR1 or BCAR3 gene in ZR-75-1 cells and have made direct comparisons with the expression changes after cell stimulation with oestrogen or epidermal growth factor (EGF) [28].

Analytical, diagnostic and therapeutic context of BCAR1


  1. BCAR1, a human homologue of the adapter protein p130Cas, and antiestrogen resistance in breast cancer cells. Brinkman, A., van der Flier, S., Kok, E.M., Dorssers, L.C. J. Natl. Cancer Inst. (2000) [Pubmed]
  2. Development of an ELISA for measurement of BCAR1 protein in human breast cancer tissue. Grebenchtchikov, N., Brinkman, A., van Broekhoven, S.P., de Jong, D., Geurts-Moespot, A., Span, P.N., Peters, H.A., Portengen, H., Foekens, J.A., Sweep, C.G., Dorssers, L.C. Clin. Chem. (2004) [Pubmed]
  3. Immunohistochemical study of the BCAR1/p130Cas protein in non-malignant and malignant human breast tissue. van der Flier, S., van der Kwast, T.H., Claassen, C.J., Timmermans, M., Brinkman, A., Henzen-Logmans, S.C., Foekens, J.A., Dorssers, L.C. Int. J. Biol. Markers (2001) [Pubmed]
  4. Melanoma chondroitin sulphate proteoglycan regulates cell spreading through Cdc42, Ack-1 and p130cas. Eisenmann, K.M., McCarthy, J.B., Simpson, M.A., Keely, P.J., Guan, J.L., Tachibana, K., Lim, L., Manser, E., Furcht, L.T., Iida, J. Nat. Cell Biol. (1999) [Pubmed]
  5. Crk-associated substrate p130(Cas) interacts with nephrocystin and both proteins localize to cell-cell contacts of polarized epithelial cells. Donaldson, J.C., Dempsey, P.J., Reddy, S., Bouton, A.H., Coffey, R.J., Hanks, S.K. Exp. Cell Res. (2000) [Pubmed]
  6. Efficacy and tolerability of memantine in patients with dementia syndrome. A double-blind, placebo controlled trial. Ditzler, K. Arzneimittel-Forschung. (1991) [Pubmed]
  7. Effects of memantine on synaptic transmission in the hippocampus in vitro. Dimpfel, W. Arzneimittel-Forschung. (1995) [Pubmed]
  8. Bcar1/p130Cas protein and primary breast cancer: prognosis and response to tamoxifen treatment. van der Flier, S., Brinkman, A., Look, M.P., Kok, E.M., Meijer-van Gelder, M.E., Klijn, J.G., Dorssers, L.C., Foekens, J.A. J. Natl. Cancer Inst. (2000) [Pubmed]
  9. 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, L.A., Lerner, A. J. Biol. Chem. (2000) [Pubmed]
  10. Crk-associated substrate (Cas) family member, NEDD9, is regulated in human neuroblastoma cells and in the embryonic hindbrain by all-trans retinoic acid. Merrill, R.A., See, A.W., Wertheim, M.L., Clagett-Dame, M. Dev. Dyn. (2004) [Pubmed]
  11. Protein kinase C-dependent tyrosine phosphorylation of p130cas in differentiating neuroblastoma cells. Fagerström, S., Påhlman, S., Nånberg, E. J. Biol. Chem. (1998) [Pubmed]
  12. Involvement of p130(Cas) and p105(HEF1), a novel Cas-like docking protein, in a cytoskeleton-dependent signaling pathway initiated by ligation of integrin or antigen receptor on human B cells. Manié, S.N., Beck, A.R., Astier, A., Law, S.F., Canty, T., Hirai, H., Druker, B.J., Avraham, H., Haghayeghi, N., Sattler, M., Salgia, R., Griffin, J.D., Golemis, E.A., Freedman, A.S. J. Biol. Chem. (1997) [Pubmed]
  13. 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) [Pubmed]
  14. The structural basis of localization and signaling by the focal adhesion targeting domain. Arold, S.T., Hoellerer, M.K., Noble, M.E. Structure (Camb.) (2002) [Pubmed]
  15. 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, K.N., Near, R.I., Luo, Z., Chernoff, J., Albanese, C., Pestell, R.G., Lerner, A. Cancer Res. (2003) [Pubmed]
  16. The prognostic value of BCAR1 in patients with primary breast cancer. Dorssers, L.C., Grebenchtchikov, N., Brinkman, A., Look, M.P., van Broekhoven, S.P., de Jong, D., Peters, H.A., Portengen, H., Meijer-van Gelder, M.E., Klijn, J.G., van Tienoven, D.T., Geurts-Moespot, A., Span, P.N., Foekens, J.A., Sweep, F.C. Clin. Cancer Res. (2004) [Pubmed]
  17. 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, S.N., Groopman, J., Canty, T., Avraham, S., Freedman, A.S. J. Biol. Chem. (1997) [Pubmed]
  18. Critical Role of Vimentin Phosphorylation at Ser-56 by p21-activated Kinase in Vimentin Cytoskeleton Signaling. Li, Q.F., Spinelli, A.M., Wang, R., Anfinogenova, Y., Singer, H.A., Tang, D.D. J. Biol. Chem. (2006) [Pubmed]
  19. Celecoxib induces anoikis in human colon carcinoma cells associated with the deregulation of focal adhesions and nuclear translocation of p130Cas. Casanova, I., Parreño, M., Farré, L., Guerrero, S., Céspedes, M.V., Pavon, M.A., Sancho, F.J., Marcuello, E., Trias, M., Mangues, R. Int. J. Cancer (2006) [Pubmed]
  20. BCAR1/p130Cas expression in untreated and acquired tamoxifen-resistant human breast carcinomas. van der Flier, S., Chan, C.M., Brinkman, A., Smid, M., Johnston, S.R., Dorssers, L.C., Dowsett, M. Int. J. Cancer (2000) [Pubmed]
  21. Association of PTP-PEST with the SH3 domain of p130cas; a novel mechanism of protein tyrosine phosphatase substrate recognition. Garton, A.J., Burnham, M.R., Bouton, A.H., Tonks, N.K. Oncogene (1997) [Pubmed]
  22. Shear stress stimulation of p130(cas) tyrosine phosphorylation requires calcium-dependent c-Src activation. Okuda, M., Takahashi, M., Suero, J., Murry, C.E., Traub, O., Kawakatsu, H., Berk, B.C. J. Biol. Chem. (1999) [Pubmed]
  23. Dietary protein induces endothelin-mediated kidney injury through enhanced intrinsic acid production. Wesson, D.E., Nathan, T., Rose, T., Simoni, J., Tran, R.M. Kidney Int. (2007) [Pubmed]
  24. Engagement of the NG2 proteoglycan triggers cell spreading via rac and p130cas. Majumdar, M., Vuori, K., Stallcup, W.B. Cell. Signal. (2003) [Pubmed]
  25. Extracellular-regulated kinase activation and CAS/Crk coupling regulate cell migration and suppress apoptosis during invasion of the extracellular matrix. Cho, S.Y., Klemke, R.L. J. Cell Biol. (2000) [Pubmed]
  26. Paxillin interactions. Turner, C.E. J. Cell. Sci. (2000) [Pubmed]
  27. Activation of Wiskott-Aldrich syndrome protein and its association with other proteins by stromal cell-derived factor-1alpha is associated with cell migration in a T-lymphocyte line. Okabe, S., Fukuda, S., Broxmeyer, H.E. Exp. Hematol. (2002) [Pubmed]
  28. Breast cancer oestrogen independence mediated by BCAR1 or BCAR3 genes is transmitted through mechanisms distinct from the oestrogen receptor signalling pathway or the epidermal growth factor receptor signalling pathway. Dorssers, L.C., van Agthoven, T., Brinkman, A., Veldscholte, J., Smid, M., Dechering, K.J. Breast Cancer Res. (2005) [Pubmed]
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