Abstract
Abstract According to the American Cancer Society, breast cancer is the second leading cause of cancer-related deaths in American women, with more than 200,000 new cases diagnosed annually. In addition, the vast majority of breast cancers are initially hormone-dependent and 70% are estrogen receptor (ER)-positive (Colditz, J. Natl. Cancer Inst., 1998; Hankinson et al., Breast Cancer Res., 2004; and Harvey et al., J. Clin. Oncol., 1999), highlighting the importance of estrogen signaling pathways in breast oncogenesis. It has been well-established that estrogen/17β-estradiol/E2 stimulates cell growth and inhibits apoptosis in ER-positive breast cancer cells; however, recent reports have demonstrated that E2 paradoxically induces the expression of Noxa/PMAIP1, a BH3-only pro-apoptotic member of the Bcl-2 family. In the present study, we report on the mechanisms by which E2 upregulates Noxa expression and the associated cellular effects on apoptosis and cell cycle progression in ER-positive MCF7 human breast cancer cells. We demonstrate that c-Myc, ERα, and E2F1 are involved in the transcriptional upregulation of Noxa following E2 treatment. Specific knockdown of c-Myc and ERα protein expression using siRNA technology inhibited E2-mediated induction of Noxa expression. Furthermore, E2 also promoted the recruitment of c-Myc and ERα to the NOXA promoter in chromatin immunoprecipitation (ChIP) assays, suggesting that these two proteins are indeed mediators of Noxa upregulation following E2 treatment. Although p53 is an important regulator of Noxa transcription under conditions of cellular stress, our data demonstrate that E2-mediated upregulation of Noxa is a p53-independent process, as knocking down p53 with specific siRNA did not block E2-mediated induction of Noxa. Consistent with this result, E2 treatment failed to induce the recruitment of p53 to the NOXA promoter in ChIP assays. Interestingly, E2-mediated upregulation of Noxa was associated with cell cycle progression but not with apoptosis under normal, unstressed cellular conditions. Cell cycle analysis by flow cytometry showed that siRNA-mediated knockdown of Noxa caused cell cycle arrest in G0/G1-phase and significantly delayed the G1-to-S-phase transition following E2 treatment. Collectively, these data indicate that Noxa expression is required for cell cycle progression in ER-positive breast cancer cells, suggesting a novel role for the BH3-only protein Noxa, outside of its traditional role as an apoptosis sensitizer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2054. doi:1538-7445.AM2012-2054
Published Version
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call