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, 86 (6), 879-85

The Human Ovarian Surface Epithelium Is an Androgen Responsive Tissue

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The Human Ovarian Surface Epithelium Is an Androgen Responsive Tissue

R J Edmondson et al. Br J Cancer.

Abstract

The pathogenesis of epithelial ovarian cancer remains unclear. From epidemiological studies raised levels of androgens have been implicated to increase the risk of developing the disease. The purpose of this study was to determine the responses of normal human ovarian surface epithelium to androgens. We have established primary cultures of human ovarian surface epithelium from patients undergoing oophorectomy for benign disease. Total RNA was isolated from these cultures and expression of mRNA encoding for the androgen receptor was demonstrated using reverse transcriptase polymerase chain reaction. The presence of androgen receptor in sections of normal ovary was also investigated using an antibody against androgen receptor. The effects of androgens on DNA synthesis and cell death were determined. Eight out of eight (100%) cultures expressed mRNA encoding the androgen receptor. The presence of androgen receptor in ovarian surface epithelium of sections of normal ovaries was demonstrated in all sections. Mibolerone, a synthetic androgen, caused a significant stimulation of DNA synthesis in 5 out of 9 (55%) cultures when used at a concentration of 1 nM. Mibolerone also caused a significant decrease in cell death in 2 out of 5 (40%) cultures tested. We have demonstrated that the ovarian surface epithelium is an androgen responsive tissue and that androgens can cause an increase in proliferation and a decrease in cell death. These findings have important implications for the pathophysiology of ovarian carcinogenesis.

Figures

Figure 4
Figure 4
The effects of mibolerone on cells from a primary culture of human ovarian surface epithelium (hOSE 45). Tritiated thymidine was added after the addition of growth factor or 10% serum. Cells were harvested 24 h later. The assay was performed with six replicates. ** Denotes significantly increased DNA synthesis than cells in serum free medium (P<0.01 t-test).
Figure 1
Figure 1
Ovarian surface epithelium in monolayer culture. (A) Photomicrograph of normal OSE grown in monolayer culture demonstrating typical appearance of epithelial phenotype. (B) Photomicrograph of methanol-fixed OSE cells stained with cytokeratin-18 anti-serum to confirm epithelial phenotype of the cultures.
Figure 2
Figure 2
Reverse transcriptase PCR of mRNA extracted from eight primary cultures of normal OSE showing expression of mRNA encoding for androgen receptor compared to expression of the constitutive gene GAP-DH.
Figure 3
Figure 3
Androgen receptor expression in sections of normal human ovary and fallopian tube. (A) Section of normal fallopian tube showing strong epithelial expression of the androgen receptor. (B) Androgen receptor positive granulosa (G) and stromal (S) cells in a developing follicle within normal ovary. (C) Androgen receptor positive OSE cells lining a normal ovary. (D) Androgen receptor negative OSE cells from a different patient lining a normal ovary. (E) Androgen receptor positive epithelium within an inclusion cyst in normal ovary. (F) Cytokeratin positive OSE in normal ovary demonstrating epithelial phenotype.
Figure 5
Figure 5
Effect of adding mibolerone to cultures of the ovarian cancer cell lines 41M and MDAH. Tritiated thymidine was added to the cultures immediately following addition of mibolerone and the cells were harvested 24 h later. The increase in DNA synthesis was significantly greater than cells in serum free medium with a dose of 100 pM in both cultures (P<0.02, t-test).
Figure 6
Figure 6
The effect of mibolerone on cell death of OSE cells for five cultures of hOSE exposed to 100 nM and 1 nM mibolerone. The effects of staurosporin, an inducer of apoptosis are shown for comparison. * Denotes significantly more/less cell death than cells in serum free medium P<0.05, ** Denotes significantly more/less cell death than cells in serum free medium P<0.01.

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