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.

journal_name

Endocr Relat Cancer

journal_title

Endocrine-related cancer

authors

Karmakar S,Foster EA,Blackmore JK,Smith CL

doi

10.1677/ERC-09-0285

subject

Has Abstract

pub_date

2010-12-21 00:00:00

pages

113-27

issue

1

eissn

1351-0088

issn

1479-6821

pii

ERC-09-0285

journal_volume

18

pub_type

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