Document Detail

Distinctive functions of p160 steroid receptor coactivators in proliferation of an estrogen-independent, tamoxifen-resistant breast cancer cell line.
MedLine Citation:
PMID:  21059860     Owner:  NLM     Status:  MEDLINE    
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.
Sudipan Karmakar; Estrella A Foster; Julia K Blackmore; Carolyn L Smith
Publication Detail:
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.     Date:  2010-12-21
Journal Detail:
Title:  Endocrine-related cancer     Volume:  18     ISSN:  1479-6821     ISO Abbreviation:  Endocr. Relat. Cancer     Publication Date:  2011 Feb 
Date Detail:
Created Date:  2010-12-23     Completed Date:  2011-04-27     Revised Date:  2013-07-03    
Medline Journal Info:
Nlm Unique ID:  9436481     Medline TA:  Endocr Relat Cancer     Country:  England    
Other Details:
Languages:  eng     Pagination:  113-27     Citation Subset:  IM    
Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
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MeSH Terms
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
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
Grant Support
Reg. No./Substance:
0/Estrogen Receptor Modulators; 0/Nuclear Receptor Coactivators; 10540-29-1/Tamoxifen; 22X328QOC4/fulvestrant; 50-28-2/Estradiol; EC protein, human; EC Receptor Coactivator 3

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