Abstract
The mechanisms of metastatic progression from hormonal therapy (HT) are largely unknown in luminal breast cancer. Here we demonstrate the enrichment of CD133hi/ERlo cancer cells in clinical specimens following neoadjuvant endocrine therapy and in HT refractory metastatic disease. We develop experimental models of metastatic luminal breast cancer and demonstrate that HT can promote the generation of HT-resistant, self-renewing CD133hi/ERlo/IL6hi cancer stem cells (CSCs). HT initially abrogates oxidative phosphorylation (OXPHOS) generating self-renewal-deficient cancer cells, CD133hi/ERlo/OXPHOSlo. These cells exit metabolic dormancy via an IL6-driven feed-forward ERlo-IL6hi-Notchhi loop, activating OXPHOS, in the absence of ER activity. The inhibition of IL6R/IL6-Notch pathways switches 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.
Highlights
The mechanisms of metastatic progression from hormonal therapy (HT) are largely unknown in luminal breast cancer
Discrepancies in cancer stem cells (CSCs) phenotypes and abundance are quite variable in clinical specimens, suggesting that CSCs likely evolve with primary tumour growth, with metastatic progression and in response to therapies[4,5]
Decreased expression of ER, increased circulating interleukin 6 (IL6) levels and the presence of circulating CSCs have independently been associated with metastatic progression in breast cancer patients[11,12,13], no models have been proposed to explain their role in endocrine-resistant disease
Summary
The mechanisms of metastatic progression from hormonal therapy (HT) are largely unknown in luminal breast cancer. We develop experimental models of metastatic luminal breast cancer and demonstrate that HT can promote the generation of HT-resistant, self-renewing CD133hi/ERlo/IL6hi cancer stem cells (CSCs). Decreased expression of ER, increased circulating interleukin 6 (IL6) levels and the presence of circulating CSCs have independently been associated with metastatic progression in breast cancer patients[11,12,13], no models have been proposed to explain their role in endocrine-resistant disease. In this manuscript, we developed the hypothesis that resistance to hormonal therapy (HT) occurs through a change in the selfrenewal capacity of metastases, evolving from an ER-dependent to an ER-independent one. These observations led to therapeutic interventions reversing HT-resistant diseases
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