Abstract LB-236: Self-renewal of CD133hi cells by IL6/Notch3 signaling regulates endocrine resistance in metastatic breast cancers

Abstract

Abstract The mechanisms of metastatic progression from hormonal therapy (HT)-induced tumour dormancy to hormonal therapy resistance is largely unknown in luminal breast cancer. Analysis of clinical specimens revealed the enrichment of CD133hi/ERlo cancer cells in primary tumours following neo-adjuvant endocrine therapy and in HT refractory metastatic disease. We developed spontaneous experimental models of metastatic luminal breast cancer and determined that endocrine therapy can promote the generation of HT- resistant, self-renewing CD133hi/ERlo/IL6hicells. Dual pharmacological inhibition of IL6R-IL6 (tocilizumab) and ER (HT) abrogated the establishment of CD133hi/ERlo/IL6hi cancer stem cells (CSCs), restoring endocrine sensitivity to hormone-refractory metastatic disease, in both experimental and patient-derived endocrine-resistant bone metastasis. Hormonal therapy, initially abrogated oxidative phosphorylation (OXPHOS) generating dormant (self-renewal deficient-CD133hi/ERlo/OXPHOSlo) cancer cells, These cells exited metabolic dormancy via an IL6 driven feed-forward ERlo-IL6hi-Notchhi loop, activating OXPHOS, in the absence of ER activity. Importantly, the inhibition of IL6R/IL6-Notch pathways switched the self-renewal of CD133hi CSCs, from an IL6/Notch-dependent one to an ER-dependent one, through the re-expression of ER. Thus, HT induces an OXPHOS metabolic editing of luminal breast cancers, paradoxically establishing HT-driven self-renewal of dormant CD133hi/ERlo cells mediating metastatic progression, which is sensitive to dual targeted therapy. Citation Format: Pasquale Sansone, Ceccarelli Claudio, Marjan Berishaj, Qing Chang, Rajasekhar Vinagolu, Fabiana Perna, Robert Bowman, Michele Vidone, Laura Daly, Jennifer Nnoli, Donatella Santini, Taffurelli Mario, Natalie Shih, Michael Feldman, Jun James Mao, Christopher Colameco, Jinbo Chen, Angela DeMichele, Nicola Fabbri, John Healey, Monica Cricca, Giuseppe Gasparre, David Lyden, Massimiliano Bonafe, Jacqueline F. Bromberg. Self-renewal of CD133hi cells by IL6/Notch3 signaling regulates endocrine resistance in metastatic breast cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-236.