Antiprogestins reduce epigenetic field cancerization in breast tissue of young healthy women (vol 14, 64, 2022)

被引：1

作者：

Bartlett, Thomas E. ^{[1
]}

Evans, Iona ^{[2
]}

Jones, Allison ^{[2
]}

Barrett, James E. ^{[2
,3
,4
]}

Haran, Shaun ^{[2
]}

Reisel, Daniel ^{[2
]}

Papaikonomou, Kiriaki ^{[5
,6
]}

Jones, Louise ^{[7
]}

Herzog, Chiara ^{[3
,4
]}

Pashayan, Nora ^{[8
]}

Simoes, Bruno M. ^{[9
]}

Clarke, Robert B. ^{[9
]}

Evans, D. Gareth ^{[10
,11
]}

Ghezelayagh, Talayeh S. ^{[12
,13
]}

Ponandai-Srinivasan, Sakthivignesh ^{[6
]}

Boggavarapu, Nageswara R. ^{[5
,6
]}

Lalitkumar, Parameswaran G. ^{[5
,6
]}

Howell, Sacha J. ^{[14
]}

Risques, Rosa Ana ^{[12
]}

Radestad, Angelique Floter ^{[5
,6
]}

Dubeau, Louis ^{[15
]}

Gemzell-Danielsson, Kristina ^{[5
,6
]}

Widschwendter, Martin ^{[2
,3
,4
,5
,6
]}

机构：

[1] UCL, Dept Stat Sci, London WC1E 7HB, England

[2] UCL, UCL EGA Inst Womens Hlth, Dept Womens Canc, 74 Huntley St, London WC1E 6AU, England

[3] Univ Innsbruck, European Translat Oncol Prevent & Screening EUTOP, A-6060 Hall In Tirol, Austria

[4] Univ Innsbruck, Res Inst Biomed Aging Res, A-6020 Innsbruck, Austria

[5] Karolinska Inst, Div Obstet & Gynecol, Dept Womens & Childrens Hlth, Stockholm, Sweden

[6] Karolinska Univ Hosp, Stockholm, Sweden

[7] Queen Mary Univ London, Barts Canc Inst, Ctr Tumour Biol Dept, London, England

[8] UCL, Dept Appl Hlth Res, 1-19 Torrington Pl, London WC1E 7HB, England

[9] Univ Manchester, Fac Biol Med & Hlth, Div Canc Sci, Breast Biol Grp,Manchester Breast Ctr, Manchester, Lancs, England

[10] Univ Manchester, St Marys Hosp, Manchester, Lancs, England

[11] Univ Hosp South Manchester, Manchester, Lancs, England

[12] Univ Washington, Dept Lab Med & Pathol, Seattle, WA 98195 USA

[13] Univ Washington, Dept Obstet & Gynecol, Seattle, WA 12 USA

[14] Christie NHS Fdn Trust, Dept Med Oncol, Manchester, Lancs, England

[15] Univ Southern Calif, USC Norris Comprehens Canc Ctr, Keck Sch Med, Dept Pathol, Los Angeles, CA 90007 USA

来源：

GENOME MEDICINE | 2022年 / 14卷 / 01期

关键词：

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

D O I：

10.1186/s13073-022-01086-y

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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. © 2022, The Author(s).

引用

页数：2