Antiprogestins reduce epigenetic field cancerization in breast tissue 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 antagonising progesterone can prevent breast cancers in humans. We suggest that targeting progesterone signalling could be a means of reducing features which are known to promote breast cancer formation. METHODS: In healthy premenopausal women with and without a BRCA mutation we studied (i) estrogen and progesterone levels in saliva over an entire menstrual cycle (n = 20); (ii) cancer-free normal breast-tissue from a control population who had no family or personal history of breast cancer and equivalently from BRCA1/2 mutation carriers (n = 28); triple negative breast cancer (TNBC) biopsies and healthy breast tissue taken from sites surrounding the TNBC in the same individuals (n = 14); and biopsies of ER+ve/PR+ve stage T1-T2 cancers and healthy breast tissue taken from sites surrounding the cancer in the same individuals (n = 31); 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; n = 44). 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, 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. TRIAL REGISTRATION: Clinical trial 1 Mifepristone treatment prior to insertion of a levonorgestrel releasing intrauterine system for improved bleeding control - a randomized controlled trial, clinicaltrialsregister.eu, 2009-009014-40 ; registered on 20 July 2009. Clinical trial 2 The effect of a progesterone receptor modulator on breast tissue in women with BRCA1 and 2 mutations, clinicaltrials.gov, NCT01898312 ; registered on 07 May 2013. Clinical trial 3 A pilot prevention study of the effects of the anti- progestin Ulipristal Acetate (UA) on surrogate markers of breast cancer risk, clinicaltrialsregister.eu, 2015-001587-19 ; registered on 15 July 2015.

Polyethylene glycated leukemia inhibitory factor antagonist inhibits human blastocyst implantation and triggers apoptosis by down-regulating embryonic AKT.

OBJECTIVE: To study the effect of polyethylene glycated leukemia inhibitory factor (LIF) antagonist (PEGLA) in the human blastocyst viability and implantation process. DESIGN: In vitro study. SETTING: University hospital and research laboratory. PATIENT(S): Endometrial biopsy samples from fertile donors (n = 20), and surplus, frozen, good-quality human embryos obtained from an in vitro fertilization (IVF) clinic that survived thawing (n = 51). INTERVENTION(S): Timed human endometrial biopsy on the day of luteinizing hormone peak + 4 days (LH + 4). MAIN OUTCOME MEASURE(S): Human embryo attachment rate, embryo quality, and expression of AKT and caspase-3. RESULT(S): PEGLA significantly reduced the embryo attachment rate to the endometrial construct. It decreased both mRNA and protein for LIF in the endometrial construct. Inhibition of embryonic LIF triggered apoptosis. Analysis of these blastocysts by immunofluorescence and real-time polymerase chain reaction showed a down-regulation in AKT activation and an increase in caspase-3 activation compared with the control group of blastocysts. CONCLUSION(S): The LIF inhibitor PEGLA could be a potential nonsteroidal fertility-regulating agent in humans. It acts on endometrial epithelial cells by down-regulating endometrial epithelial LIF. Inhibition of blastocyst LIF decreased its cell survival factor p-AKT and increased apoptosis (cleaved caspase-3). This highlights that embryonic LIF is vital for human embryo implantation.