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Downregulation of 15-hydroxyprostaglandin dehydrogenase during acquired tamoxifen resistance and association with poor prognosis in ERα-positive breast cancer
- Source :
- Exploration of Targeted Anti-tumor Therapy, Vol 1, Iss 5, Pp 355-371 (2020), Exploration of targeted anti-tumor therapy
- Publication Year :
- 2020
- Publisher :
- Open Exploration Publishing Inc., 2020.
-
Abstract
- Aim: Tamoxifen (TAM) resistance remains a clinical issue in breast cancer. The authors previously reported that 15-hydroxyprostaglandin dehydrogenase (HPGD) was significantly downregulated in tamoxifen-resistant (TAMr) breast cancer cell lines. Here, the authors investigated the relationship between HPGD expression, TAM resistance and prediction of outcome in breast cancer. Methods: HPGD overexpression and silencing studies were performed in isogenic TAMr and parental human breast cancer cell lines to establish the impact of HPGD expression on TAM resistance. HPGD expression and clinical outcome relationships were explored using immunohistochemistry and in silico analysis. Results: Restoration of HPGD expression and activity sensitised TAMr MCF-7 cells to TAM and 17β-oestradiol, whilst HPGD silencing in parental MCF-7 cells reduced TAM sensitivity. TAMr cells released more prostaglandin E2 (PGE2) than controls, which was reduced in TAMr cells stably transfected with HPGD. Exogenous PGE2 signalled through the EP4 receptor to reduce breast cancer cell sensitivity to TAM. Decreased HPGD expression was associated with decreased overall survival in ERα-positive breast cancer patients. Conclusions: HPGD downregulation in breast cancer is associated with reduced response to TAM therapy via PGE2-EP4 signalling and decreases patient survival. The data offer a potential target to develop combination therapies that may overcome acquired tamoxifen resistance.
- Subjects :
- 0301 basic medicine
lcsh:Internal medicine
EP4 Receptor
survival
Article
endocrine resistance
03 medical and health sciences
0302 clinical medicine
Breast cancer
breast cancer
Downregulation and upregulation
medicine
Gene silencing
Prostaglandin E2
skin and connective tissue diseases
lcsh:RC31-1245
business.industry
Transfection
15-hydroxyprostaglandin dehydrogenase
medicine.disease
030104 developmental biology
030220 oncology & carcinogenesis
immunohistochemistry
Cancer research
Immunohistochemistry
business
Tamoxifen
hormones, hormone substitutes, and hormone antagonists
medicine.drug
Subjects
Details
- Language :
- English
- ISSN :
- 26923114
- Volume :
- 1
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- Exploration of Targeted Anti-tumor Therapy
- Accession number :
- edsair.doi.dedup.....6d435acab5cfa5b892d2be20a631dc8e