• Open Access

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

Authors

  • Olga Grechukhina,

    1. Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA
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  • Rafaella Petracco,

    1. Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA
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    • These authors contributed equally to this work.

  • Shota Popkhadze,

    1. Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA
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    • These authors contributed equally to this work.

  • Efi Massasa,

    1. Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA
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  • Trupti Paranjape,

    1. Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT, USA
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  • Elcie Chan,

    1. Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT, USA
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  • Idhaliz Flores,

    1. Departments of Microbiology and of Obstetrics and Gynecology, Ponce School of Medicine and Health Sciences, Ponce, PR, USA
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  • Joanne B. Weidhaas,

    Corresponding author
    1. Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT, USA
    • Joanne B. Weidhaas, Tel: 203-737-4267; Fax: 203-785-6309

      Hugh S. Taylor, Tel: +1 203-785-4005; Fax: +1 203-785-7819

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  • Hugh S. Taylor

    Corresponding author
    1. Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA
    2. Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT, USA
    • Joanne B. Weidhaas, Tel: 203-737-4267; Fax: 203-785-6309

      Hugh S. Taylor, Tel: +1 203-785-4005; Fax: +1 203-785-7819

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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.

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