A polymorphism in a let-7 microRNA binding site of KRAS in women with endometriosis.
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.
Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA.
Olga
O
Grechukhina
Rafaella
R
Petracco
Shota
S
Popkhadze
Efi
E
Massasa
Trupti
T
Paranjape
Elcie
E
Chan
Idhaliz
I
Flores
Joanne B
JB
Weidhaas
Hugh S
HS
Taylor
D000328:Adult; D000483:Alleles; D000818:Animals; D001665:Binding Sites; D004715:Endometriosis / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D017154:Stromal Cells / Q000378:metabolism; D055815:Young Adult; D018631:ras Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
C117307:KRAS protein, human; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; C487931:mirnlet7 microRNA, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins