Cyclin dependent kinase-9 mediated transcriptional de-regulation of cMYC as a critical determinant of endocrine-therapy resistance in breast cancers

Surojeet Sengupta, Michael C Biarnes, V Craig Jordan
Breast Cancer Research and Treatment 2014, 143 (1): 113-24
Endocrine therapy resistance in estrogen receptor alpha positive (ERα+) breast cancers remains a major obstacle for maintaining efficacy of targeted therapies. We investigated the significance and the mechanisms involved in cMYC over-expression in a MCF7 derived panel of ERα+ breast cancer cells which can proliferate in the absence of estrogen with different sensitivities to anti-hormone therapies. We show that all the resistant cell lines tested over-express cMYC as compared to parental MCF7 cells and its inhibition lead to the differential blocking of estrogen-independent proliferation in resistant cells. Further investigation of the resistant cell line, MCF7:5C, suggested transcriptional de-regulation of cMYC gene was responsible for its over-expression. Chromatin immuno-precipitation assay revealed markedly higher recruitment of phosphorylated serine-2 carboxy-terminal domain (CTD) of RNA polymerase-II at the proximal promoter of cMYC gene, which is responsible for transcriptional elongation of the cMYC RNA. The level of CDK9, a factor responsible for the phosphorylation of serine-2 of RNA polymerase II CTD, was found to be elevated in all the resistant cell lines. Pharmacological inhibition of CDK9 not only reduced the transcripts and the protein levels of cMYC in MCF7:5C cells but also selectively inhibited the estrogen-independent growth of all the resistant cell lines. This study describes the up-stream molecular events involved in the transcriptional over-expression of cMYC gene in breast cancer cells proliferating estrogen-independently and identifies CDK9 as a potential novel drug target for therapeutic intervention in endocrine-resistant breast cancers.

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