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

Abstract

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 α (ERα) ligands. Surprisingly, the effects of SRC coactivator depletion on ERα transcriptional activity, as measured by luciferase reporter gene, did not correspond to the observed effects on proliferation (e.g. SRC-1 knockdown increases ERα activity). Collectively, these data indicate that SRC control of basal and hormone-regulated proliferations is not solely mediated by ERα, 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.

• Authors: Sudipan Karmakar, Estrella A Foster, Julia K Blackmore, Carolyn L Smith
• Journal: Endocrine-related cancer (Endocr Relat Cancer) Vol. 18 Issue 1 Pg. 113-27 (Feb 2011) ISSN: 1479-6821 [Electronic] England
• PMID: 21059860 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Estrogen Receptor Modulators
• Nuclear Receptor Coactivators
• Tamoxifen
• Fulvestrant
• Estradiol
• NCOA3 protein, human
• Nuclear Receptor Coactivator 3

Topics

• Breast Neoplasms (genetics, metabolism, pathology)
• Carcinoma (genetics, metabolism, pathology)
• Cell Line, Tumor
• Cell Proliferation
• Drug Resistance, Neoplasm (drug effects, genetics)
• Estradiol (analogs & derivatives, pharmacology)
• Estrogen Receptor Modulators (pharmacology)
• Female
• Fulvestrant
• Humans
• Multigene Family (genetics, physiology)
• Nuclear Receptor Coactivator 3 (genetics, metabolism, physiology)
• Nuclear Receptor Coactivators (genetics, metabolism, physiology)
• Tamoxifen (pharmacology, therapeutic use)
• Transcriptional Activation (drug effects, genetics)