Glucocorticoid induced loss of oestrogen receptor alpha gene methylation and restoration of sensitivity to fulvestrant in triple negative breast cancer

Haya Intabli, Julia Gee, steffi Oesterreich, Mark Yeoman, Marcus Allen, Amal Qattan, Melanie Flint

Research output: Contribution to journalArticlepeer-review


The response to psychological stress can differ depending on the type and duration of the stressor. Acute stress can facilitate a "fight or flight response" and aid survival, whereas chronic long-term stress with the persistent release of stress hormones such as cortisol has been shown to be detrimental to health. We are now beginning to understand how this stress hormone response impacts important processes such as DNA repair and cell proliferation processes in breast cancer. However, it is not known what epigenetic changes stress hormones induce in breast cancer. Epigenetic mechanisms include modification of DNA and histones within chromatin that may be involved in governing the transcriptional processes in cancer cells in response to changes by endogenous stress hormones. The contribution of endogenous acute or long-term exposure of glucocorticoid stress hormones, and exogenous glucocorticoids to methylation patterns in breast cancer tissues with different aetiologies remains to be evaluated. In vitro and in vivo models were developed to investigate the epigenetic modifications and their contribution to breast cancer progression and aetiology. A panel of triple negative breast cancer cell lines were treated with the glucocorticoid, cortisol which resulted in epigenetic alteration characterised by loss of methylation on promoter regions of tumour suppressor genes including ESR1, and loss of methylation on LINE-1 repetitive element used as a surrogate marker for global methylation. This was verified in vivo in MDA-MB-231 xenografts; the model verified the loss of methylation on ESR1 promoter, and subsequent increase in ESR1 expression in primary tumours in mice subjected to restraint stress. Our study highlights that DNA methylation landscape in breast cancer can be altered in response to stress and glucocorticoid treatment.
Original languageEnglish
Article number147022
Publication statusPublished - 5 Nov 2022

Bibliographical note

Funding Information:
We would like to acknowledge Somesh Singh at the University Hospitals Sussex NHS Foundation Trust for assessing the immunohistrochemestry (IHC) of oestrogen receptor (ER). We would also like to acknowledge Andra Antohi from University of Brighton for help in IHC imaging. Conception and design: MSF. HI. JG. SO. AQ Development of methodology: HI. MSF Acquisition of data: HI Statistical analysis: HI, MSY Writing, review, and/or revision of the manuscript: HI. JG. SO. MY. MCA. AQ. MSF.

Publisher Copyright:
© 2022 The Authors


  • Breast cancer
  • Epigenetics
  • Methylation
  • Stress


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