期刊
NATURE GENETICS
卷 49, 期 3, 页码 444-450出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.3773
关键词
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资金
- Associazione Italiana Ricerca sul Cancro (AIRC)
- Imperial College Junior Research Fellowship
- Cancer Research UK (CRUK) grant [C37/A18784]
- CRUK PhD studentship [P55374]
- EpiPredict project (European Union's Horizon research and innovation program under the Marie Sklodowska-Curie grant agreement) [642691]
- Cancer Research UK [18784] Funding Source: researchfish
Tumor evolution is shaped by many variables, potentially involving external selective pressures induced by therapies(1). After surgery, patients with estrogen receptor (ER alpha)-positive breast cancer are treated with adjuvant endocrine therapy2, including selective estrogen receptor modulators (SERMs) and/or aromatase inhibitors (Als)(3). However, more than 20% of patients relapse within 10 years and eventually progress to incurable metastatic disease(4). Here we demonstrate that the choice of therapy has a fundamental influence on the genetic landscape of relapsed diseases. We found that 21.5% of Al-treated, relapsed patients had acquired CYP19A1 (encoding aromatase) amplification (CYP19Al(amp)). Relapsed patients also developed numerous mutations targeting key breast cancer associated genes, including ESR1 and CYP19A1. Notably, CYP19A l(amp) cells also emerged in vitro, but only in Al-resistant models. CYP19A1 amplification caused increased aromatase activity and estrogen-independent ER alpha binding to target genes, resulting in CYP19A/(amp) cells showing decreased sensitivity to Al treatment. These data suggest that Al treatment itself selects for acquired CYP19A/(amp) and promotes local autocrine estrogen signaling in Al-resistant metastatic patients.
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