Acquired CYP19A1 amplification is an early specific mechanism of aromatase inhibitor resistance in ERα metastatic breast cancer

Luca Magnani, Gianmaria Frigè, Raffaella Maria Gadaleta, Giacomo Corleone, Sonia Fabris, Hermannus Kempe, Pernette J. Verschure, Iros Barozzi, Valentina Vircillo, Sung Pil Hong, Ylenia Perone, Massimo Saini, Andreas Trumpp, Giuseppe Viale, Antonino Neri, Simak Ali, Marco Angelo Colleoni, Giancarlo Pruneri, Saverio Minucci

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Abstract

Tumor evolution is shaped by many variables, potentially involving external selective pressures induced by therapies. After surgery, patients with estrogen receptor (ERα)-positive breast cancer are treated with adjuvant endocrine therapy, including selective estrogen receptor modulators (SERMs) and/or aromatase inhibitors (AIs). However, more than 20% of patients relapse within 10 years and eventually progress to incurable metastatic disease. 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 AI-treated, relapsed patients had acquired CYP19A1 (encoding aromatase) amplification (CYP19A1 amp). Relapsed patients also developed numerous mutations targeting key breast cancer-associated genes, including ESR1 and CYP19A1. Notably, CYP19A1 amp cells also emerged in vitro, but only in AI-resistant models. CYP19A1 amplification caused increased aromatase activity and estrogen-independent ERα binding to target genes, resulting in CYP19A1 amp cells showing decreased sensitivity to AI treatment. These data suggest that AI treatment itself selects for acquired CYP19A1 amp and promotes local autocrine estrogen signaling in AI-resistant metastatic patients.

Original languageEnglish
Pages (from-to)444-450
Number of pages7
JournalNature Genetics
Volume49
Issue number3
DOIs
Publication statusPublished - Mar 1 2017

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ASJC Scopus subject areas

  • Genetics

Cite this

Magnani, L., Frigè, G., Gadaleta, R. M., Corleone, G., Fabris, S., Kempe, H., Verschure, P. J., Barozzi, I., Vircillo, V., Hong, S. P., Perone, Y., Saini, M., Trumpp, A., Viale, G., Neri, A., Ali, S., Colleoni, M. A., Pruneri, G., & Minucci, S. (2017). Acquired CYP19A1 amplification is an early specific mechanism of aromatase inhibitor resistance in ERα metastatic breast cancer. Nature Genetics, 49(3), 444-450. https://doi.org/10.1038/ng.3773