Expression of stromal progesterone receptor and differential methylation patterns in the endometrium may correlate with response to progesterone therapy in endometrial complex atypical hyperplasia
Open accessAbstract
Progesterone therapy is a viable treatment for complex atypical hyperplasia (CAH) and endometrial adenocarcinoma, though reliable molecular determinants of response are not available. To explore if analysis of pre-therapy endometrial biopsies could yield biomarkers of response to progesterone, patients with CAH or adenocarcinoma undergoing treatment with progestins were included in this cross-sectional study. Immunohistochemistry for progesterone receptor (PR) was performed. Manual PR expression scores (PRES) were first calculated for biopsies by counting PR-positive nuclei in 12 sensitive vs 9 resistant samples. Significant differences in manual PRES were detected in the stroma (p < 0.01) and total endometrium (p < 0.01) for sensitive vs resistant patients. Manual PRES in the stroma had the highest accuracy in segregating sensitive vs resistant patients (96%). Differences in epithelial PRES were not significant. To validate these findings, a correlation between manual PRES and visual PRES was performed in the 21 patients. An additional 11 patients were analyzed to test if visual PRES would be predictive of response to progesterone. Visual PRES in epithelia and stroma in the 32 specimens was calculated. Significant differences in visual PRES were detected in the stroma for sensitive vs resistant samples (p < 0.01), while differences in epithelial and total endometrium were not significant. Whole genome bisulfite sequencing was performed on DNA isolated using pre-therapy biopsies from 6 sensitive and 6 resistant patients in this cohort. Differentially methylated regions were identified in the stroma and epithelium when evaluating sensitive vs resistant samples. Pathways involved in cell adhesion demonstrated the greatest difference in methylation in these samples.
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These endometrial cells exhibit hypermethylation of the PR-B promoter, inducing expression of the receptor protein and resulting in progesterone resistance.
“these endometrial cells also exhibit hypermethylation of the PR-B promoter, inducing expression of the receptor protein [38,39,40] and finally resulting in a state of progesterone resistance.”
From Endometriosis and Medical Therapy: From Progestogens to Progesterone Resistance to GnRH Antagonists: A Review (2021) · cites this paper as [38]
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Donnez, J., & Dolmans, M.-M. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10051085 · Cited by 182 · see citing works
- Authors
- Neal, A. S., Nunez, M., Lai, T., Tosevska, A., Morselli, M., Amneus, M., Zakhour, M., Moatamed, N. A., Pellegrini, M., & Memarzadeh, S.
- Affiliations
- University of California, Los Angeles (US)
- University of California, San Francisco (US)
- Kaiser Permanente (US)
- Corresponding author
- Memarzadeh, Sanaz
- Venue
- Reproductive Sciences
- Published
- 2020-03-02
- Volume
- 27
- Issue
- 9
- Pages
- 1778-1790
- ISSN
- 1933-7191 (ISSN-L)
- 1933-7205
- PMC
- PMC7395059
- OpenAlex
- W3009059990
- Cited by
- 11
- References
- 44
- Citations by year
- 2024: 5 · 2023: 3 · 2022: 2 · 2021: 1
- FWCI
- 0.92
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Reproductive Sciences (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- National Cancer Institute (R01CA183877, P50CA211015, P30CA016042)
- Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California Los Angeles
- Topics
- Health Sciences › Medicine › Obstetrics and Gynecology › Endometrial and Cervical Cancer Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
- Keywords
- progesterone receptor, endometrial adenocarcinoma, endometrial stroma, DNA methylation, differentially methylated regions, treatment response biomarkers, cell adhesion pathway, progestin resistance
- MeSH terms
- Adult, Cross-Sectional Studies, Endometrial Hyperplasia, Endometrium, Female, Humans, Immunohistochemistry, Progesterone, Receptors, Progesterone, Stromal Cells, DNA Methylation
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