Identification of aberrant luminal progenitors and mTORC1 as a potential breast cancer prevention target in BRCA2 mutation carriers

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发表日期：

2024年1月12日

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Rachel Joyce,
Rosa Pascual,
Luuk Heitink,
Bianca D. Capaldo,
François Vaillant,
Michael Christie,
Minhsuang Tsai,
Elliot Surgenor,
Casey J. A. Anttila,
Pradeep Rajasekhar,
Felicity C. Jackling,
Marie Trussart,
Michael J. G. Milevskiy,
Xiaoyu Song,
Mengbo Li,
Charis E. Teh,
Daniel H. D. Gray,
Gordon K. Smyth,
Yunshun Chen,
Geoffrey J. Lindeman,
Jane E. Visvader

摘要

Inheritance of a BRCA2 pathogenic variant conveys a substantial life-time risk of breast cancer. Identification of the cell(s)-of-origin of BRCA2-mutant breast cancer and targetable perturbations that contribute to transformation remains an unmet need for these individuals who frequently undergo prophylactic mastectomy. Using preneoplastic specimens from age-matched, premenopausal females, here we show broad dysregulation across the luminal compartment in BRCA2^mut/+ tissue, including expansion of aberrant ERBB3^lo luminal progenitor and mature cells, and the presence of atypical oestrogen receptor (ER)-positive lesions. Transcriptional profiling and functional assays revealed perturbed proteostasis and translation in ERBB3^lo progenitors in BRCA2^mut/+ breast tissue, independent of ageing. Similar molecular perturbations marked tumours bearing BRCA2-truncating mutations. ERBB3^lo progenitors could generate both ER⁺ and ER⁻ cells, potentially serving as cells-of-origin for ER-positive or triple-negative cancers. Short-term treatment with an mTORC1 inhibitor substantially curtailed tumorigenesis in a preclinical model of BRCA2-deficient breast cancer, thus uncovering a potential prevention strategy for BRCA2 mutation carriers.