Antiprogestins reduce epigenetic field cancerization in breast tissue of young healthy women

Thomas E Bartlett, Iona Evans, Allison Jones, James E Barrett, Shaun Haran, Daniel Reisel, Kiriaki Papaikonomou, Louise Jones, Chiara Herzog, Nora Pashayan, Bruno M Simões, Robert B Clarke, D Gareth Evans, Talayeh S Ghezelayagh, Sakthivignesh Ponandai-Srinivasan, Nageswara R Boggavarapu, Parameswaran G Lalitkumar, Sacha J Howell, Rosa Ana Risques, Angelique Flöter Rådestad, Louis Dubeau, Kristina Gemzell-Danielsson, Martin Widschwendter, Thomas E Bartlett, Iona Evans, Allison Jones, James E Barrett, Shaun Haran, Daniel Reisel, Kiriaki Papaikonomou, Louise Jones, Chiara Herzog, Nora Pashayan, Bruno M Simões, Robert B Clarke, D Gareth Evans, Talayeh S Ghezelayagh, Sakthivignesh Ponandai-Srinivasan, Nageswara R Boggavarapu, Parameswaran G Lalitkumar, Sacha J Howell, Rosa Ana Risques, Angelique Flöter Rådestad, Louis Dubeau, Kristina Gemzell-Danielsson, Martin Widschwendter

Abstract

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.

Keywords: Antiprogestins; BRCA1; Breast cancer; DNA methylation; Epigenetics; Intermediate surrogate marker; Prevention.

Conflict of interest statement

RAR owns equity and serves as a scientific consultant to TwinStrand Biosciences Inc. UCLB (UCL's commercialisation company) has filed a patent on some aspects described in the paper – MW is named as inventor on this patent. JEB, CH and MW are shareholders of Sola Diagnostics GmbH, which holds an exclusive licence to the intellectual property described in this patent file. The remaining authors declare that they have no competing interests.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Summary of the rationale and design of the study. Abbreviations: mut (mutation); wt (wild-type); pcgt (polycomb-group targets); NB (normal breast); CO (control); BB (breast biopsy); BC (breast cancer)
Fig. 2
Fig. 2
Effect of the BRCA1/2 mutation carrier states on estradiol and progesterone levels during menstrual cycle progression. Estradiol and progesterone hormone levels were significantly greater over one cycle in BRCA1/2 mutation carriers (n = 12) than in controls (n = 8): a and b show the time-series (respectively) for estradiol and progesterone (normalised by cycle length) with one-week moving average lines. c One-week moving windows (as used to plot the moving average lines in a and b) were used to assess how the relative increase in hormone levels in BRCA1/2 mutation carriers (compared to controls) varies during the cycle. All significances were assessed with t-tests
Fig. 3
Fig. 3
WID-Breast29 score in triple negative breast cancer (TNBC) and adjacent normal tissues. a The WID-Breast29 score is based on 37 CpGs from 29 genes and b was significantly greater in normal breast tissue surrounding TNBC (n = 14) when compared to normal tissue from cancer-free women (n = 14); significance was assessed with the t-test. c The WID-Breast29 score also increased significantly when transitioning from normal surrounding tissue to TNBC (n = 14) or d ER+ve/PR+ve breast cancer (n = 31); gold lines indicate increasing and blue decreasing values from surround normal to the cancer tissue in individual breast cancer patients; significance was assessed with the paired-sample t-test. e The WID-Breast29 score was also significantly associated with patient survival outcome in 257 TCGA breast cancer samples (after adjusting for covariates); significance was assessed by z-tests on the Wald statistics after fitting a multivariate Cox proportional hazards model
Fig. 4
Fig. 4
Assessment of breast epithelium composition in TNBC. a Fractional composition of breast-tissue samples was assessed using a well-validated algorithm [37], based on our custom-designed DNAme reference profiles for breast epithelial cell subtypes (Materials and Methods). b There was a highly significant increase in luminal progenitor cell concentration in TNBC (compared to normal surrounding tissue in the same volunteers, n = 14), whereas c the mature luminal cell proportion was unchanged and the d basal cell fraction decreased. e Comparing normal tissues in the same volunteers (n = 31) to ER+ve/PR+ve breast cancers, there was a decrease in luminal progenitors and f a highly significant increase in mature luminal cells and g no changes were noted in basal cells; gold lines indicate increasing and blue decreasing values from surround normal to the cancer tissue in individual breast cancer patients (b-g). h RANKL and i RANK expression (respectively) were significantly correlated with mature luminal and luminal progenitor cell proportion in 38 healthy breast tissue samples from TCGA; j the mean of the normalised RANKL and RANK expression levels was significantly correlated with the WID-Breast29 index in the same 38 samples. Significances in b–g were assessed with the paired-sample t-test, and those in h–j were assessed with Pearson’s correlation test. F, Fat cells; I, Immune cells; E, Epithelial cells; S, Stromal cells; LP, Luminal Progenitors; LM, Luminal Mature; B, Basal
Fig. 5
Fig. 5
Effects of vitamins (placebo/comparator), mifepristone and ulipristal acetate treatment on intermediate cancer surrogate endpoints in normal breast tissue from healthy women. The impact of Vitamin (a–c), Mifepristone (d–f) and Ulipristal acetate (h–j) on the mitotic age index WID-Breast29 (a, d, h), luminal progenitor cell fraction (b, e, i) and basal cell fraction (c, f, j) in healthy, unaffected women at lower and higher breast cancer risk. g RANKL mRNA expression before and after treatment with mifepristone (as assessed by real-time PCR). k Correlation of the change in WID-Breast29 index with the change in breast epithelial subtype fractions in all samples in a–f, h–j. All significances in a–j were assessed with the paired-sample t-test. Significance in k was assessed with Pearson’s correlation test. Gold lines indicate increasing and blue lines decreasing values from the breast biopsy taken before to biopsy taken after treatment
Fig. 6
Fig. 6
Mifepristone treatment and the dynamics of TP53 mutations in normal breast tissue and suggested model for the prevention of triple negative breast cancer. aTP53 mutation frequency and bTP53 mutation count in normal breast tissue before and after mifepristone exposure in women who showed a decrease of the WID-Breast29 index after mifepristone (responders) and who did not show a decrease (non-responders); significance was assessed with the two-sided t-test. c Progesterone triggers release of RANKL in hormone receptor (HR) positive mature luminal cells leading to increased proliferation and thus accelerated mitotic ageing in HR negative luminal progenitor cells resulting in increased cancer risk; these effects are reduced after treatment with the progesterone antagonist mifepristone. HR, hormone receptor

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