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.
We thank Werbena Hamilton-Burke, Loaie Maraqa and Mark Peter for providing clinical data on the breast tumours which populated the TMAs used in this study.
This work was supported in part by Cancer Research UK grant C13432/A9047; Yorkshire Cancer Research grant L314; the Robert Bosch Foundation, Stuttgart, Germany; the NIH; MD Anderson’s Cancer Center support grant CA016672; the George and Barbara Bush Foundation for Innovative Cancer Research; and the Dallas/Fort Worth Living Legend Chair of Cancer Research. The study sponsor(s) played no part in the study design; in the collection, analysis and interpretation of the data; in the writing of the report; and in the decision to submit the paper for publication.
- Breast cancer
- endocrine resistance
- 15-hydroxyprostaglandin dehydrogenase