Utilising an in vitro breast cancer prevention model in order to develop intermediate surrogate endpoints

Cancer development is a multifactorial process that occurs at various stages in life and sometimes decades in advance of diagnosis.

Current preventive measures for women at high risk - including anti-estrogens and prophylactic bilateral mastectomy - are either inadequate or unfavorable and new approaches are needed.

A greater understanding of the biological mechanisms underlying breast cancer development will enable new strategies to prevent and monitor the disease.Based on extensive preliminary data, the hypothesis to be investigated in this 3-year project is that both progesterone (+/- estrogen) and hypoxia drive (i) the expansion of luminal progenitor cells; and (ii) trigger alterations at the level of the genome and the epigenome.

The net effect of progesterone / hypoxia exposure is an accumulation of luminal progenitor cells which have accumulated a high replicative age and (epi) genetic alterations reminiscent of triple negative breast cancer cells.

The presence of mifepristone (but not tamoxifen) and / or the forced expression of BRCA1 is able to prevent these progesterone / hypoxia mediated changes.We will use 3D organoid cell models established using human breast epithelial cells from women with genetic mutations placing them at higher risk of developing breast cancer ( BRCA1 mutations) alongside cutting edge techniques including single cell RNA sequencing, ultra-accurate duplex DNA sequencing and DNA methylation analysis.