A polymorphism in a let‐7 microRNA binding site of KRAS in women with endometriosis

Abstract

Endometriosis is found in 5–15% of women of reproductive age and is more frequent in relatives of women with the disease. Activation of KRAS results in de novo endometriosis in mice, however, activating KRAS mutations have not been identified in women. We screened 150 women with endometriosis for a polymorphism in a let-7 microRNA (miRNA) binding site in the 3'-UTR of KRAS and detected a KRAS variant allele in 31% of women with endometriosis as opposed to 5% of a large diverse control population. KRAS mRNA and protein expression were increased in cultured endometrial stromal cells of women with the KRAS variant. Increased KRAS protein was due to altered miRNA binding as demonstrated in reporter assays. Endometrial stromal cells from women with the KRAS variant showed increased proliferation and invasion. In a murine model, endometrial xenografts containing the KRAS variant demonstrated increased proliferation and decreased progesterone receptor levels. These findings suggest that an inherited polymorphism of a let-7 miRNA binding site in KRAS leads to abnormal endometrial growth and endometriosis. The LCS6 polymorphism is the first described genetic marker of endometriosis risk.

Aromatase inhibitor regulates let-7 expression and let-7f–induced cell migration in endometrial cells from women with endometriosis

“…Interestingly, an association between decreased expression of several let-7 subtypes and endometriosis has been reported recently (10,12). Let-7b expression, associated with cyclin D1, an estrogen-regulated gene involved in cellular proliferation, was significantly lower in patients with endometriosis than controls, and several let-7 subtypes in sera and HESC from patients with endometriosis were also shown to be down-regulated (7, 9). Our results indicate that among let-7 subtypes, let-7f is associated with letrozole treatment in Ishikawa cells and in HESC.…”

“…However, there is insufficient data concerning the detailed molecular mechanisms of AI in endometriosis. Since dysregulation of miRNAs has been recently reported to play a key role in various therapeutic responses (16), and there is a growing body of evidence indicating possible involvement of miRNAs in the pathogenesis of endometriosis (5–9), we hypothesized that AI treatment may involve alteration of miRNAs in endometriosis. Potential involvement of miRNAs in the treatment of AI has been suggested in breast cancer cell lines.…”

“…Among several miRNAs that are dysregulated in endometriosis, an association of miRNA let-7 and endometriosis has been suggested recently. In some women with severe endometriosis, a polymorphism of a let-7 miRNA binding site in the KRAS 3′ UTR leads to abnormal endometrial cell KRAS expression and that endometrial and circulating let-7 family members were expressed at lower levels in patients with endometriosis (7, 9). Based on these previous findings, we hypothesized a possible involvement of let-7 in endometriosis and in response to AI treatment.…”

Estrogen withdrawal, increased breast cancer risk and the KRAS-variant

“…S1), consistent with prior reports in KRAS-variant-associated tissues. 39 WT and MT lines were plated in soft agar to test for transformation, as measured by anchorage independent growth. There was no colony formation seen in the presence of Epidermal Growth Factor (EGF) during the course of the experiment for either the WT or MT lines, indicating that neither line, at baseline, was transformed (Fig.…”

The role of Lipoxin A4 in endometrial biology and endometriosis

“…Let-7 miRNA was one of those most upregulated in the endometrium of women with endometriosis 196 and intruigingly, a let-7 miRNA polymorphism has been associated with endometriosis. 198 Let-7 miRNAs inhibit IL-13 expression. 199 …”