Abstract B089: The suppression of ERa activity promotes the mitochondrial deficient CD133hi/Notch3hi/ERalow cancer stem cell phenotype via autocrine IL6 in luminal breast cancer

The inhibition of ERa pathway (hormonal therapy -HT-) is the most effective therapeutic strategy for metastatic luminal breast cancer. However, the efficacy of HT is time-limited, suggesting that metastatic disease will eventually employ an ERa-independent biochemistry. Here we demonstrated that CD133 hi /CD44 low tumor initiating cells arise following ERa lack of function via oxidative phosphorylation (OXPHOS) dysfunction. These cells display a remarkable migrating and metastatic phenotype, which associate with the downregulation of ERa and the increased expression of Notch3. Chronic lack of ERa activity by tamoxifen generates CD133 hi /Notch3 hi /ERal ow via the up-regulation of tumor-derived IL6. We then showed that IL6 confers resistance to ERa lack of function by up-regulating glycolysis/OXPHOS. Finally, higher expression of CD133, Notch3 and IL6 identifies ERa low luminal breast cancers endowed with metastatic and self-renewal potentials. In conclusion, our data demonstrate that oxidative phosphorylation dysfunction and autocrine IL6 are key molecular triggers of intra-tumor heterogeneity and tumor initiating capabilities in luminal breast cancer refractory to anti ERa target therapy. Citation Format: Pasquale Sansone, Massimiliano Bonafe, Claudio Ceccarelli, Marjan Berishaj, Jacqueline Bromberg. The suppression of ERa activity promotes the mitochondrial deficient CD133 hi /Notch3 hi /ERa low cancer stem cell phenotype via autocrine IL6 in luminal breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr B089.