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

Joyce, R; Pascual, R; Heitink, L; Capaldo, BD; Vaillant, F; Christie, M; Tsai, M; Surgenor, E; Anttila, CJA; Rajasekhar, P; Jackling, FC; Trussart, M; Milevskiy, MJG; Song, X; Li, M; Teh, CE; Gray, DHD; kConFab, Consortium; Smyth, GK; Chen, Y; Lindeman, GJ; Visvader, JE

Author(s): Joyce, R; Pascual, R; Heitink, L; Capaldo, BD; Vaillant, F; Christie, M; Tsai, M; Surgenor, E; Anttila, CJA; Rajasekhar, P; Jackling, FC; Trussart, M; Milevskiy, MJG; Song, X; Li, M; Teh, CE; Gray, DHD; kConFab, Consortium; Smyth, GK; Chen, Y; Lindeman, GJ; Visvader, JE;
Details: Publication Year 2024-01,Volume 26,Issue #1,Page 138-152
Journal Title: Nature Cell Biology
Abstract: 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.
Publisher: NPG
Keywords: Female; Humans; *Breast Neoplasms/genetics/prevention & control; Mastectomy; Mutation; BRCA2 Protein/genetics; Carcinogenesis; Cell Transformation, Neoplastic; BRCA1 Protein/genetics
Research Division(s): Advanced Technology And Biology; Bioinformatics; Blood Cells And Blood Cancer; Immunology; Personalised Oncology; Cancer Biology And Stem Cells
PubMed ID: 38216737
Publisher's Version: https://doi.org/10.1038/s41556-023-01315-5
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-01-25 09:18:01

Last Modified: 2024-01-25 10:46:02