Estrogen receptor ? isoform 5 confers sensitivity of breast cancer cell lines to chemotherapeutic agent-induced apoptosis through interaction with Bcl2L12.

ABSTRACT: Alternative splicing of estrogen receptor ? (ER?) yields five isoforms, but their functions remain elusive. ER? isoform 5 (ER?5) has been positively correlated with better prognosis and longer survival of patients with breast cancer (BCa) in various clinical studies. In this study, we investigated the inhibitory role of ER?5 in BCa cells. Although ER?5 does not reduce proliferation of BCa cell lines MCF-7 and MDA-MB-231, its ectopic expression significantly decreases their survival by sensitizing them to doxorubicin- or cisplatin-induced apoptosis through the intrinsic apoptotic pathway. Moreover, we discovered Bcl2L12, which belongs to the Bcl-2 family regulating apoptosis, to be a specific interacting partner of ER?5, but not ER?1 or ER?, in an estradiol-independent manner. Knockdown of Bcl2L12 enhanced doxorubicin- or cisplatin-induced apoptosis, and this process was further promoted by ectopic expression of ER?5. Whereas Bcl2L12 was previously shown to inhibit apoptosis through binding to caspase 7, such interaction is reduced in the presence of ER?5, suggesting a mechanism by which ER?5 sensitizes cells to apoptosis. In conclusion, ER?5 interacts with Bcl2L12 and functions in a novel estrogen-independent molecular pathway that promotes chemotherapeutic Agent-Induced in vitro apoptosis of BCa cell lines.

SUBMITTER: Lee MT 

PROVIDER: S-EPMC3858893 | biostudies-other | 2013 Nov

REPOSITORIES: biostudies-other