Flash Talk and Poster Presentation 36th Lorne Cancer Conference 2024

Identification of aberrant luminal progenitors and mTORC1 as a potential breast cancer prevention target in BRCA2 mutation carriers (#106)

Rachel Joyce 1 2 , Rosa Pascual 1 2 , Luuk Heitink 1 2 , Francois Vaillant 1 2 , Amy Tsai 1 , Elliot Surgenor 1 , Casey Anttila 3 , Felicity Jackling 1 , Michael Milevskiy 1 2 , Shirley (Xiaoyu) Song 1 2 , Mengbo Li 2 4 , Gordon Smyth 4 5 , Yunshun Chen 1 2 5 , Geoffrey Lindeman 1 6 7 , Jane Visvader 1 2
  1. ACRF Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute, Parkville, VIC, Australia
  2. Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia
  3. Advanced Technology and Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  4. Bioinformatics Division, The Walter and Eliza Hall Institute, Parkville, VIC, Australia
  5. School of Mathematics and Statistics, The University of Melbourne, Parkville, VIC, Australia
  6. Department of Medicine, Royal Melbourne Hospital , The University of Melbourne, Parkville, VIC, Australia
  7. Parkville Familial Cancer Centre, Royal Melbourne Hospital and Peter MacCallum Cancer Centre, Parkville, VIC, Australia

Inheritance of a BRCA2 pathogenic variant conveys a significant 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, pre-menopausal females, here we show broad dysregulation across the luminal compartment in BRCA2mut/+ tissue, including expansion of aberrant ERBB3lo luminal progenitor and mature cells. Transcriptional profiling and functional assays revealed perturbed proteostasis and translation in ERBB3lo progenitors in BRCA2mut/+ breast tissue, independent of aging. Similar molecular perturbations marked tumours bearing BRCA2-truncating mutations. ERBB3lo 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.