期刊
NATURE COMMUNICATIONS
卷 7, 期 -, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/ncomms10442
关键词
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资金
- Department of Defense [W81XWH-10-1-1013]
- National Institutes of Health [R01: CA87637, U01-CA169538, R01: CA158243, KG110876]
- Charles and Marjorie Holloway Foundation
- Sussman Family Fund
- Lerner Foundation
- AstraZeneca
- Breast Cancer Alliance
- Manhasset Women's Coalition Against Breast Cancer
- NYS Women's Bowling Association
- Beth C. Tortolani Foundation
- MSK Cancer Center Support Grant/Core Grant [P30 CA008748]
- Manning Foundation
- Hartwell Foundation
- Fundacao para aCiencia e a Tecnologia
- Nancy C and Daniel P Paduano Foundation
- Mary Kay Foundation
- Pediatric Oncology Experimental Therapeutic Investigator Consortium (POETIC)
- James Paduano Foundation
- Malcolm Hewitt Weiner Foundation
- Theodore A Rapp Foundation
- American Hellenic Educational Progressive Association 5th District Cancer Research Foundation
- Associazione Italiana Ricerca sul Cancro (AIRC) [IG14242]
- Fondazione Umberto Veronesi (grant DISCO TRIP)
- FP7 EU ITN-Marie Curie Action project MEET [317433]
- triennial AIRC fellowship 'Wanda Cantone e Alberto Rigillo'
- Cornelia and Roberto Pallotti Legacy
The mechanisms of metastatic progression from hormonal therapy (HT) are largely unknown in luminal breast cancer. Here we demonstrate the enrichment of CD133(hi)/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 CD133(hi)/ERlo/IL6(hi) cancer stem cells (CSCs). HT initially abrogates oxidative phosphorylation (OXPHOS) generating self-renewal-deficient cancer cells, CD133(hi)/ERlo/OXPHOSlo. These cells exit metabolic dormancy via an IL6-driven feed-forward ERlo-IL6(hi)-Notch(hi) loop, activating OXPHOS, in the absence of ER activity. The inhibition of IL6R/IL6-Notch pathways switches the self-renewal of CD133(hi) 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 CD133(hi)/ERlo cells mediating metastatic progression, which is sensitive to dual targeted therapy.
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