Abstract
BackgroundThe fallopian tube epithelium is one of the potential sources of high-grade serous ovarian cancer (HGSC). The use of estrogen only hormone replacement therapy increases ovarian cancer (OVCA) risk. Despite estrogen’s influence in OVCA, selective estrogen receptor modulators (SERMs) typically demonstrate only a 20 % response rate. This low response could be due to a variety of factors including the loss of estrogen receptor signaling or the role of estrogen in different potential cell types of origin. The response of fallopian tube epithelium to SERMs is not known, and would be useful when determining therapeutic options for tumors arising from this cell type, such as HGSC.ResultsUsing normal murine derived oviductal epithelial cells (mouse equivalent to the fallopian tube) estrogen receptor expression was confirmed and interaction with its ligand, estradiol, triggered mRNA and protein induction of progesterone receptor (PR). The SERMs 4-hydroxytamoxifen, raloxifene and desmethylarzoxifene, functioned as estrogen receptor antagonists in oviductal cells. Cellular proliferation and migration assays suggested that estradiol does not significantly impact cellular migration and increased proliferation. Further, using RNAseq, the oviduct specific transcriptional genes targets of ER when stimulated by estradiol and 4-hydroxytamoxifen signaling were determined and validated. The RNA-seq revealed enrichment in proliferation, anti-apoptosis, calcium signaling and steroid signaling processes. Finally, the ER and PR receptor status of a panel of HGSC cell lines was investigated including Kuramochi, OVSAHO, OVKATE, OVCAR3, and OVCAR4. OVSAHO demonstrated receptor expression and response, which highlights the need for additional models of ovarian cancer that are estrogen responsive.ConclusionsOverall, the fallopian tube has specific gene targets of estrogen receptor and demonstrates a tissue specific response to SERMs consistent with antagonistic action.Electronic supplementary materialThe online version of this article (doi:10.1186/s13048-016-0213-3) contains supplementary material, which is available to authorized users.
Highlights
The fallopian tube epithelium is one of the potential sources of high-grade serous ovarian cancer (HGSC)
To investigate the role of estrogen signaling in this precursor cell type of HGSC, we evaluated the response of murine oviductal epithelium (MOE) cells derived from CD1 and FVB murine backgrounds subjected to 17-beta-estradiol (E2) treatment (Fig. 1a, b)
The disappearance of Estrogen receptor α (ERα) via proteasome–mediated proteolysis [26], and upregulation of the canonical ER regulated target progesterone receptor (PRA and PRB, two isoforms encoded by the Pgr gene) were monitored for E2 responsiveness via Western blot analysis
Summary
The fallopian tube epithelium is one of the potential sources of high-grade serous ovarian cancer (HGSC). The use of estrogen only hormone replacement therapy increases ovarian cancer (OVCA) risk. Despite estrogen’s influence in OVCA, selective estrogen receptor modulators (SERMs) typically demonstrate only a 20 % response rate. This low response could be due to a variety of factors including the loss of estrogen receptor signaling or the role of estrogen in different potential cell types of origin. The response of fallopian tube epithelium to SERMs is not known, and would be useful when determining therapeutic options for tumors arising from this cell type, such as HGSC. Risk factors for non-heritable OVCA include null parity, infertility, the number of lifetime ovulations and the use of estrogen only-hormone replacement therapy [8]. Given the recent findings suggesting that OVCA is increased by hormone replacement therapy containing estrogen and the fallopian tube may be the source of HGSC, the estrogen receptor targets in the fallopian tube should be defined [12]
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