Poster Presentation 35th Lorne Cancer Conference 2023

Interrogating the cell-of-origin of BRCA2 mutant breast cancer to identify novel targets for chemoprevention (#202)

Rachel Joyce 1 2 , Rosa Pascual 1 2 , Luuk Heitink 1 2 , Francois Vaillant 1 2 , Yunshun Chen 1 2 , Gordon Smyth 3 4 , Geoff Lindeman 1 5 6 7 , Jane Visvader 1 2
  1. ACRF Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, Australia, Parkville
  2. Department of Medical Biology, The University of Melbourne, Australia, Parkville
  3. Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Australia, Parkville
  4. School of Mathematics and Statistics, The University of Melbourne, Australia, Parkville
  5. The Royal Melbourne Hospital, Australia, Parkville
  6. The Peter MacCallum Cancer Centre, Australia, Melbourne
  7. Department of Medicine, The University of Melbourne, Australia, Parkville

It is currently estimated that approximately one woman dies every minute of breast cancer across the globe. While the greatest risk factor for developing breast or ovarian cancer is having female reproductive organs, the cumulative life-time risk of developing breast and ovarian cancer for women who carry pathogenic mutations in their BRCA2 gene is significantly higher than non-carriers. To date, there have been no prospective studies or chemoprevention trials for breast cancer development in BRCA2 mutation carriers-as such, there is a pressing need for the identification of novel therapeutic pathways for breast cancer prevention in these patients. Transcriptional profiling coupled with downstream ex vivo functional assays were used to interrogate preneoplastic breast epithelium from BRCA2 mutation carriers and non-carriers, revealing dysregulation across the luminal compartment and an expansion of aberrant luminal progenitors in premenopausal  BRCA2mut/+ breast tissue. These data uncover a perturbed cell signalling pathway within preneoplastic breast epithelium of premenopausal BRCA2 mutation carriers, and describe developments in our understanding of the cellular alterations present in BRCA2mut/+ mammary epithelium that may predispose to breast cancer development.