Disease relevance of BCAR1

• In this study, we isolated and characterized the crucial gene at the breast cancer antiestrogen resistance 1 (BCAR1) locus [1].
• BACKGROUND: High concentrations of breast cancer anti-estrogen resistance 1 (BCAR1) protein measured by Western blotting in primary breast tumor cytosols are associated with early disease progression and failure of tamoxifen therapy [2].
• Using antibodies raised against the rat p130Cas protein, we determined by immunohistochemical methods the BCAR1/p130Cas localization in primary breast carcinomas, in tumors of stromal origin, and in non-neoplastic breast tissues [3].
• Melanoma chondroitin sulphate proteoglycan regulates cell spreading through Cdc42, Ack-1 and p130cas [4].
• A yeast two-hybrid screen using the C-terminal region of Cas as a bait identified the Src homology 3 (SH3) domain of the mouse "nephrocystin" protein-orthologous to a human protein whose loss of function leads to the cystic kidney disease familial juvenile nephronophthisis [5].

Psychiatry related information on BCAR1

• The efficacy and tolerability of memantine (1-amino-3,5-dimethyl-adamantane hydrochloride, Akatinol Memantine; CAS 41100-52-1) was investigated in a double-blind, randomized clinical study versus placebo in 66 patients aged between 65 and 80 years predominantly suffering from mild to moderate vascular dementia [6].
• CA1 pyramidal cell response (population spike) in the hippocampal slice preparation was monitored after electrical stimulation of the Schaffer collaterals at CA2 in the presence of different concentrations of memantine (1-amino-3,5-dimethyladamantane, Akatinol Memantine, CAS 41100-52-1) currently being prescribed for the treatment of e.g. dementia [7].

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

• Work by others has implicated both the human homologue of AND-34, BCAR3, and human p130(Cas), BCAR1, in the resistance of breast cancer cells to the anti-estrogen tamoxifen [9].
• BCAR1/p130Cas is a docking protein involved in intracellular signaling pathways and in vitro resistance of estrogen-dependent breast cancer cells to antiestrogens [3].
• Double immunohistochemical staining for BCAR1/p130Cas and estrogen receptor confirmed coexpression in non-malignant luminal epithelial cells and malignant breast tumor cells [3].
• Crk-associated substrate (Cas) family member, NEDD9, is regulated in human neuroblastoma cells and in the embryonic hindbrain by all-trans retinoic acid [10].
• Protein kinase C-dependent tyrosine phosphorylation of p130cas in differentiating neuroblastoma cells [11].

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

• Overexpression of either of the human homologues of AND-34 and p130Cas, BCAR3 and BCAR1, respectively, has been reported to induce resistance to antiestrogens in breast cancer cell lines [15].
• RESULTS: In tumor cytosols, BCAR1 protein levels varied between 0.02 and 23 ng/mg protein [16].
• This immunohistochemical study demonstrates a variable expression of BCAR1/p130Cas in malignant and non-malignant breast epithelial cells, which may be of benefit for diagnostic purposes [3].
• The stromal cells in non-malignant tissues and tumor tissues as well as breast tumors of mesodermal origin did not stain for BCAR1/p130Cas [3].
• The related adhesion focal tyrosine kinase is tyrosine-phosphorylated after beta1-integrin stimulation in B cells and binds to p130cas [17].

Associations of BCAR1 with chemical compounds

• One of the tyrosine-phosphorylated substrates after integrin stimulation in fibroblasts is p130cas, which can associate with p125FAK [17].
• Furthermore, stimulation with 5-HT resulted in the dissociation of Crk-associated substrate (CAS; an adapter protein associated with smooth muscle force development) from cytoskeletal vimentin [18].
• We report that the deregulation of the focal adhesion assembly protein Crk-associated substrate 130 kDa (p130Cas) by celecoxib plays a relevant role in the cytotoxic effect of this drug [19].
• Our results indicate that in tumour progression towards tamoxifen resistance, increase of BCAR1/p130Cas may be only one of the molecular mechanisms [20].
• However, in long term stimulated cells, herbimycin A blocked the induced phosphorylation of p130cas [11].

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

• To determine the role of c-Src in flow-stimulated phosphorylation of Cas, we transduced cells with adenovirus encoding kinase-inactive Src [22].
• We tested the hypothesis that dietary CAS induces endothelin-mediated kidney injury through augmented intrinsic acid production [23].
• Engagement of the NG2 proteoglycan triggers cell spreading via rac and p130cas [24].
• Extracellular-regulated kinase activation and CAS/Crk coupling regulate cell migration and suppress apoptosis during invasion of the extracellular matrix [25].

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

• Sequence analysis of human BCAR1 cDNA predicted a protein of 870 amino acids that was strongly homologous to rat p130Cas-adapter protein [1].
• EXPERIMENTAL DESIGN: A specific ELISA was developed to measure BCAR1 protein levels in 2593 primary breast tumor cytosols [16].
• The assay can be used to confirm and to quantitatively extend previous semiquantitative Western blot data on the prognostic and predictive value of BCAR1 in human breast cancer; it can also be applied for other diseases [2].
• Immunohistochemistry demonstrated variable intensity of BCAR1/p130Cas staining and variation in the proportion of BCAR1/p130Cas-positive epithelial tumor cells for the different breast carcinomas [3].
• These associations implicate HEF1 and Cas as important components in a cytoskeleton-linked signaling pathway initiated by ligation of beta1 integrin or BCR on human B cells [12].

References