Canonical cancer stem cell (CSC) phenotypes (D44hi/CD24locells and ALDHhi) have been documented to sustain tumor growth and resistance to conventional anticancer therapies (for example, anti-Her2 and chemotherapy/radiation therapy) in several tumor models. However, discrepancies in CSC phenotypes and abundance are quite variable in clinical specimens, suggesting that CSCs likely evolve with primary tumor growth, with metastatic progression and in response to therapies.
Indeed, the acquisition of novel genetic changes, including gain of function mutations in the ESR1 gene, loss of PTEN and discordant expression of Her2 protein, has been observed in ~20% of metastases following conventional anticancer therapies. In addition, a reduction in oestrogen receptor alpha (ER) expression as well as a discrepancy in ER levels between primary tumors and metastatic disease are often observed with the development of tamoxifen resistance without changes in Her2 expression (~80% of cases).
Although 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, no models have been proposed to explain their role in endocrine-resistant disease.
In the study authors developed the hypothesis that resistance to hormonal therapy (HT) occurs through a change in the self-renewal capacity of metastases, evolving from an ER-dependent to an ER-independent one. Researchers demonstrate the enrichment of CD133hi/ERlo cancer cells in clinical specimens following neoadjuvant endocrine therapy and in HT refractory metastatic disease. They generated experimental and patient-derived models of HT-resistant metastases and determined the evolution of a feed-forward ER-CD133-IL6R-IL6-Notch loop underlying the process of HT resistance.
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.
http://www.nature.com/ncomms/2016/160209/ncomms10442/full/ncomms10442.html
Understanding hormonal therapy resistance in breast cancer
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