Abstract B05: Inhibition of ER/Stat3 signaling pathways drive the evolution of ER+ metastatic breast cancer through the generation of ER-independent OXPHOShi self-renewing cells

A better understanding of the molecular features of the metastatic switch might reveal new cancer cell liabilities to develop novel therapeutics for metastatic cancer patients. Here we demonstrated that the generation of dormant and tumor-initiating cells takes place in the tumor microenvironment through a metabolic reprogramming in luminal (ER+) breast cancer. The expression of the surface markers interleukin 6 receptor (IL6R) and CD44 identify distinct tumor initiating and dormant cells. We demonstrated that IL6Rlo/CD44hi cells originate in hypoxic niches and self-renew following re-oxygenation via estrogen receptor alpha (ER)-dependent up-regulation of oxidative phosphorylation (OXPHOS). Conversely, IL6Rhi/Stat3hi cells are dormant populations arising in an environment defined by recurrent episodes of hypoxia/normoxia. These cells were characterized by decreased OXPHOS and ER activities. Reducing Stat3 expression resulted in cells resistant to hypoxia/re-oxygenation-mediated dormancy. Molecularly, Stat3lo cells had reduced ER signaling, high OXPHOS and increased metastatic capacity. Thus we propose that inhibition of ER/Stat3 signaling pathways drive the evolution of ER+ metastatic breast cancer through the generation of ER-independent-OXPHOShi self-renewing cancer cells.Citation Format: Pasquale Sansone, Marjan Berishaj, Qing Chang, Antonio Strillacci, Ferdinando Giacco, Jacqueline Bromberg. Inhibition of ER/Stat3 signaling pathways drive the evolution of ER+ metastatic b...
Source: Molecular Cancer Research - Category: Cancer & Oncology Authors: Tags: Signaling Pathways and Cancer Metabolism: Poster Presentations - Proffered Abstracts Source Type: research