Self-renewal of CD133hi cells by IL6/Notch3 signalling regulates endocrine resistance in metastatic breast cancer Journal Article
| Authors: | Sansone, P.; Ceccarelli, C.; Berishaj, M.; Chang, Q.; Rajasekhar, V. K.; Perna, F.; Bowman, R. L.; Vidone, M.; Daly, L.; Nnoli, J.; Santini, D.; Taffurelli, M.; Shih, N. N. C.; Feldman, M.; Mao, J. J.; Colameco, C.; Chen, J.; DeMichele, A.; Fabbri, N.; Healey, J. H.; Cricca, M.; Gasparre, G.; Lyden, D.; Bonafé, M.; Bromberg, J. |
| Article Title: | Self-renewal of CD133hi cells by IL6/Notch3 signalling regulates endocrine resistance in metastatic breast cancer |
| 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. © 2016, Nature Publishing Group. All rights reserved. |
| Keywords: | signal transduction; controlled study; human tissue; protein expression; human cell; nonhuman; mouse; phenotype; metabolism; animal tissue; gene expression; animal experiment; animal model; cancer model; cancer hormone therapy; cancer stem cell; bioactivity; interleukin 6; upregulation; cd133 antigen; estrogen receptor; hormone; breast metastasis; notch3 receptor; inhibition; cells and cell components; cancer; human; article; stem cell self-renewal; endocrine disruptor |
| Journal Title: | Nature Communications |
| Volume: | 7 |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2016-02-09 |
| Start Page: | 10442 |
| Language: | English |
| DOI: | 10.1038/ncomms10442 |
| PROVIDER: | scopus |
| PMCID: | PMC4748123 |
| PUBMED: | 26858125 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 3 March 2016 -- Source: Scopus |
