Breast cancer antiestrogen resistance-3 expression regulates breast cancer cell migration through promotion of p130Cas membrane localization and membrane ruffling.
Antiestrogens such as tamoxifen are widely used in the clinic to treat estrogen receptor-positive breast tumors. Resistance to tamoxifen can occur either de novo or develop over time in a large proportion of these tumors. Additionally, resistance is associated with enhanced motility and invasiveness in vitro. One molecule that has been implicated in tamoxifen resistance, breast cancer antiestrogen resistance-3 (BCAR3), has also been shown to regulate migration of fibroblasts. In this study, we investigated the role of BCAR3 in breast cancer cell migration and invasion. We found that BCAR3 was highly expressed in multiple breast cancer cell lines, where it associated with another protein, p130(Cas) (also known as breast cancer antiestrogen resistance-1; BCAR1), that plays a role in both tamoxifen resistance and cell motility. In cells with relatively low migratory potential, BCAR3 overexpression resulted in enhanced migration and colocalization with p130(Cas) at the cell membrane. Conversely, BCAR3 depletion from more aggressive breast cancer cell lines inhibited migration and invasion. This coincided with a relocalization of p130(Cas) away from the cell membrane and an attenuated response to epidermal growth factor stimulation that was characterized by a loss of membrane ruffles, decreased migration toward EGF, and disruption of p130(Cas)/Crk complexes. Based on these data, we propose that the spatial and temporal regulation of BCAR3/p130(Cas) interactions within the cell is important for controlling breast cancer cell motility.
Schrecengost
Randy S
RS
Department of Microbiology, University of Virginia Health System, Charlottesville, Virginia 22908, USA.
Riggins
Rebecca B
RB
Thomas
Keena S
KS
Guerrero
Michael S
MS
Bouton
Amy H
AH
D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis* / Q000235:genetics*; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement; D050719:Crk-Associated Substrate Protein / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D004815:Epidermal Growth Factor / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D020662:Guanine Nucleotide Exchange Factors; D006801:Humans; D009361:Neoplasm Invasiveness; D034622:RNA Interference; D013629:Tamoxifen / Q000494:pharmacology
D048868:Adaptor Proteins, Signal Transducing; C118588:BCAR3 protein, human; D050719:Crk-Associated Substrate Protein; D020662:Guanine Nucleotide Exchange Factors; D013629:Tamoxifen; D004815:Epidermal Growth Factor