AND-34/BCAR3 differs from other NSP homologs in induction of anti-estrogen resistance, cyclin D1 promoter activation and altered breast cancer cell morphology.
Over-expression of AND-34/BCAR3/NSP2 (BCAR3) or its binding-partner p130Cas/BCAR1 generates anti-estrogen resistance in human breast cancer lines. Here, we have compared BCAR3 to two related homologs, NSP1 and NSP3/CHAT/SHEP, with regards to expression, anti-estrogen resistance, and signaling. BCAR3 is expressed at higher levels in ERalpha-negative, mesenchymal, than in ERalpha-positive, epithelial, breast cancer cell lines. Characterization of "intermediate" epithelial-like cell lines with variable ER-alpha expression reveals that BCAR3 expression correlates with both mesenchymal and ERalpha-negative phenotypes. Levels of the BCAR3/p130Cas complex correlate more strongly with the ERalpha-negative, mesenchymal phenotype than levels of either protein alone. NSP1 and NSP3 are expressed at lower levels than BCAR3 and without correlation to ERalpha/mesenchymal status. Among NSP-transfectants, only BCAR3 transfectants induce anti-estrogen resistance and augment transcription of cyclin D1 promoter constructs. Over-expression of all homologs results in activation of Rac, Cdc42 and Akt, suggesting that these signals are insufficient to induce anti-estrogen resistance. BCAR3 but not NSP1 nor NSP3 transfectants show altered morphology, transitioning from polygonal cell groups to rounded, single cells with numerous blebs. Whereas stable over-expression of BCAR3 in MCF-7 cells does not lead to classic epithelial-to-mesenchymal transition, it does result in down-regulation of cadherin-mediated adhesion and augmentation of fibronectin expression. These studies suggest that BCAR's ability to induce anti-estrogen resistance is greater than that of other NSP homologs and may result from altered interaction of breast cancer cells with each other and the extracellular matrix.
Near
Richard I
RI
Department of Medicine, Section of Hematology and Oncology, Boston Medical Center, Boston, MA 02118, USA.
Zhang
Yujun
Y
Makkinje
Anthony
A
Vanden Borre
Pierre
P
Lerner
Adam
A
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D048430:Cell Shape; D050719:Crk-Associated Substrate Protein / Q000378:metabolism; D056741:Cyclin D; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D020847:Estrogen Receptor Modulators / Q000494:pharmacology* / Q000627:therapeutic use; D047628:Estrogen Receptor alpha / Q000032:analysis; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D020662:Guanine Nucleotide Exchange Factors; D006801:Humans; D007365:Intercellular Junctions / Q000378:metabolism; D008648:Mesoderm / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D014162:Transfection; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D018931:Antineoplastic Agents, Hormonal; C493841:BCAR1 protein, human; C118588:BCAR3 protein, human; D015820:Cadherins; D050719:Crk-Associated Substrate Protein; D056741:Cyclin D; D016213:Cyclins; D020847:Estrogen Receptor Modulators; D047628:Estrogen Receptor alpha; D005353:Fibronectins; D020662:Guanine Nucleotide Exchange Factors; C118587:SH2D3A protein, human; C118589:SH2D3C protein, human; D051057:Proto-Oncogene Proteins c-akt; D020764:cdc42 GTP-Binding Protein; D020744:rac GTP-Binding Proteins