These authors contributed equally to this work.
A polymorphism in a let-7 microRNA binding site of KRAS in women with endometriosis
Article first published online: 3 FEB 2012
Copyright © 2012 EMBO Molecular Medicine
EMBO Molecular Medicine
Volume 4, Issue 3, pages 206–217, March 2012
How to Cite
Grechukhina, O., Petracco, R., Popkhadze, S., Massasa, E., Paranjape, T., Chan, E., Flores, I., Weidhaas, J. B. and Taylor, H. S. (2012), A polymorphism in a let-7 microRNA binding site of KRAS in women with endometriosis. EMBO Mol Med, 4: 206–217. doi: 10.1002/emmm.201100200
- Issue published online: 8 MAR 2012
- Article first published online: 3 FEB 2012
- Manuscript Accepted: 12 DEC 2011
- Manuscript Revised: 7 DEC 2011
- Manuscript Received: 12 AUG 2011
- NIH. Grant Numbers: U54 HD052668, R01 HD036887
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.