Progestin significantly inhibits carcinogenesis in the mogp-TAg mouse model of fallopian tube cancer

Abstract

<h3>Objectives:</h3> Recent studies suggest the fallopian tube epithelium (FTE) harbors the precursor for high grade ovarian cancer (HGSC), creating opportunities for targeting the FTE for ovarian cancer prevention. Preclinical evidence supports progestins as ovarian cancer preventives, but the effect of progestins on the FTE has not been well characterized. <i>in vitro</i> and primate models suggest that progestins clear genetically damaged cells in the ovarian epithelium and endometrium by activating molecular pathway such as apoptosis. The mogp-TAg transgenic mouse develops neoplastic lesions such as p53 signatures and serous tubal intraepithelial carcinoma (STIC) in the fallopian tube (FT) in a similar manner to that described in human fallopian and ovarian cancers. In this study, we investigated the inhibitory effects of the progestin-Depo-medroxyprogesterone acetate (DMPA) on FT carcinogenesis in the mogp-TAg mouse. <h3>Methods:</h3> Mogp-TAg mice (10 per group) at 5 weeks of age were injected with vehicle or the progestin Depo-medroxyprogesterone acetate-DMPA (1mg/mouse). The mice were euthanized at 8 and 12 weeks of age and the reproductive tract was removed. H&E stained sections were used to histologically and pathologically characterize the FTs following treatment. In addition, immunohistochemistry and immunofluorescence were used to characterize lesions and the cell death pathway. <h3>Results:</h3> There was an increase in the number of FT epithelial and stromal p53 positive cells from 5 to 12 weeks of age in the vehicle treated mice. Histologically, the FT of the vehicle treated mice developed adenocarcinoma and/or epithelial/smooth muscle hyperplasia at 8 and 12 weeks of age. Compared to the vehicle-treated mice, the FT of the DMPA treated mice were significantly smaller at 8 weeks (p<0.005) and 12 weeks (p<0.0005) of age. In addition, there was normal distribution of ciliated cells, less nuclear pleomorphism and epithelial tufting, and a significantly lower proliferative index (Ki67) (p=0.001) in 8 week DMPA treated mice compared to vehicle. Accumulation of p53 in the FT was significantly reduced in DMPA(p<0.000005) treated mice at 8 weeks compared to vehicle. There was significantly more cleaved caspase-3 in the FT of the DMPA-treated group compared to the vehicle group. <h3>Conclusions:</h3> DMPA treatments significantly reduced the tumor burden and aberrant p53 expression in the FT of mice compared to vehicle treated animals. Our data support the hypothesis that progestins have a cytocidal effect, clearing genetically damaged cells from the fallopian tube potentially via apoptosis. These data provide evidence supporting the hypothesis that progestin may be used for prevention of ovarian cancer.