Antiprogestins reduce epigenetic field cancerization in breasts of young healthy women

Background:Breast cancer is a leading cause of death in premenopausal women. Progesterone drives expansion of luminal progenitor cells, leading to the development of poor-prognostic breast cancers. However, it is not known if antagonizing progesterone can prevent breast cancers in humans. We suggest that targeting progesterone signalling could be a means of reducing features which are known to increase towards breast cancer formation.Methods:In healthy premenopausal women with and without a BRCA mutation we studied (i) estrogen and progesterone levels over an entire menstrual cycle (Hormonal Saliva Data-Set, n = 20); (ii) cancer-free normal breast-tissue samples from a control population who had no family or personal history of breast cancer and equivalently from BRCA1/2 mutation carriers (n = 28); and from triple negative breast cancer (TNBC) biopsies as well as healthy breast tissue samples taken from sites surrounding the TNBC in the same individuals (n = 14), DNAme Set 1; and from Biopsies from ER+ve/PR+ve stage T1–T2 cancers and healthy breast tissue samples taken from sites surrounding the cancer in the same individuals (n = 31), DNAme Set 2; and (iii) DNA methylation and DNA mutations in normal breast tissue (before and after treatment) from clinical trials that assessed the potential preventative effects of vitamins and antiprogestins, mifepristone and ulipristal acetate (Clinical Trials 1–3 and DNAme Sets 3 and 4, n = 44). Clinical Trials 1–3 (‘Mifepristone treatment prior to insertion of a levonorgestrel releasing intrauterine system for improved bleeding control – a randomized controlled trial’, ‘The effect of a progesterone receptor modulator on breast tissue in women with BRCA-1 and -2 mutations’, and ‘A pilot prevention study of the effects of the anti- progestin Ulipristal Acetate (UA) on surrogate markers of breast cancer risk’) were all prospectively registered, and informed consent was obtained from all participants.Results:Daily levels of progesterone were higher throughout the menstrual cycle of BRCA1/2 mutation carriers, raising the prospect of targeting progesterone signalling as a means of cancer risk reduction in this population. Furthermore, breast field cancerization DNA methylation signatures reflective of (i) the mitotic age of normal breast epithelium and (ii) the proportion of luminal progenitor cells were increased in breast cancers (which are highly prevalent in BRCA carriers), indicating that luminal progenitor cells with elevated replicative age are more prone to malignant transformation. The progesterone receptor antagonist mifepristone reduced both the mitotic age and the proportion of luminal progenitor cells in normal breast tissue of all control women and in 64% of BRCA1/2 mutation carriers. These findings were validated by an alternate progesterone receptor antagonist, ulipristal acetate, which yielded similar results. Importantly, mifepristone reduced both the TP53 mutation frequency as well as the number of TP53 mutations in mitotic-age-responders.Conclusions:These data support the potential usage of antiprogestins for primary prevention of poor-prognostic breast cancers