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AND‐34/BCAR3 differs from other NSP homologs in induction of anti‐estrogen resistance, cyclin D1 promoter activation and altered breast cancer cell morphology
Author(s) -
Near Richard I.,
Zhang Yujun,
Makkinje Anthony,
Borre Pierre Vanden,
Lerner Adam
Publication year - 2007
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.21059
Subject(s) - biology , cancer research , cancer cell , cancer , genetics
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 ERα‐negative, mesenchymal, than in ERα‐positive, epithelial, breast cancer cell lines. Characterization of “intermediate” epithelial‐like cell lines with variable ER‐α expression reveals that BCAR3 expression correlates with both mesenchymal and ERα‐negative phenotypes. Levels of the BCAR3/p130Cas complex correlate more strongly with the ERα‐negative, mesenchymal phenotype than levels of either protein alone. NSP1 and NSP3 are expressed at lower levels than BCAR3 and without correlation to ERα/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. J. Cell. Physiol. 212:655–665, 2007. © 2007 Wiley‐Liss, Inc.