Distinctive functions of p160 steroid receptor coactivators in proliferation of an estrogen-independent, tamoxifen-resistant breast cancer cell line

Elevated expression of steroid receptor coactivator-3 (SRC-3), a member of the p160 family of nuclear receptor coactivators, has been implicated in tamoxifen resistance of breast tumors while the involvement of the two other members of this family, SRC-1 and SRC-2, is less well characterized. In this study, using small interfering RNA-based silencing, the role of each SRC coactivator in the growth of the LCC2 estrogen-independent and tamoxifen-resistant breast cancer cell line was evaluated. The loss of SRC-1, SRC-2, or SRC-3 did not significantly alter LCC2 proliferation or cell cycle distribution of 4-hydroxytamoxifen-versus vehicle-treated cells. However, depletion of SRC-2 and SRC-3, but not SRC-1, decreased basal cell proliferation and increased apoptosis. Cell cycle analyses further illustrated the divergent contributions of SRC-2 and SRC-3 with depletion of the former increasing the percentage of cells in the G(0)G(1) and sub-G(0)G(1) phases of cell cycle yet maintaining sensitivity to estradiol and ICI 182 780 antiestrogen, while SRC-3 depletion increased cells in the sub-G(0)G(1) phase and ablated response to estrogen receptor alpha (ER alpha) ligands. Surprisingly, the effects of SRC coactivator depletion on ER alpha transcriptional activity, as measured by luciferase reporter gene, did not correspond to the observed effects on proliferation (e. g. SRC-1 knockdown increases ER alpha activity). Collectively, these data indicate that SRC control of basal and hormone-regulated proliferations is not solelymediated by ER alpha, and suggest that targeting growth inhibition by disrupting SRC-2 and SRC-3 function may be an effective approach to inhibit the growth of tamoxifen-resistant breast cancer.