WNT Signaling and HBP1-Associated Functional Analysis in Uterine Leiomyoma: Potential for a Pharmacological Approach to Disease Treatment
Leiomyomas (UL) are the most common tumors in women of reproductive age, which leads to
approximately 200,000 hysterectomies annually in the United States. Although over 95% of
UL tumors are benign, they destroy the function of the uterus and cause abnormal uterine
bleeding, anemia, pelvic pain, and recurrent pregnancy loss. Activation of the WNT
pathway is well established ... read moreas a driver of cell proliferation and tumorigenesis. In UL,
cytogenetic deletion studies have shown that the chromosomal region 7q22.3 is associated
with UL in around 40% of patients. Furthermore, the tumor suppressor HBP1, an inhibitor
of Wnt signaling, is one of the 15 genes located by mapping these deletions. Because
HBP1, a repressor of Wnt signaling, lies in this minimally deleted region, we
hypothesized that decreased HBP1 expression may contribute to WNT signaling in UL. Using
patient samples obtained from hysterectomy, we showed the protein levels of
β-catenin, the signature signal in activation of Wnt signaling, increased in
leiomyoma compared to that in myometrium. Furthermore, Axin II mRNA, a common target
gene of Wnt signaling, also increased in fibroids. These results suggest activation of
WNT signaling is common in fibroid tumors. Furthermore, HBP1 also decreased in
approximately 50% of leiomyomas, consistent with the deletion studies. To identify
whether decreased HBP1 defined a unique sub-type of fibroid tumor, we undertook an
unbiased screen of UL patients using RNAseq and bioinformatics analysis to identify
global and HBP1-dependent changes in UL. As predicted by previous published work, an
ESR1-activated proliferation gene expression signature was common in all leiomyoma
samples. In tumors with normal HBP1 levels, cell cycle and GPCR signaling, cholesterol
biosynthesis related gene signatures were active compared to HBP1 low leiomyomas. In
contrast, in the HBP1-low tumors, WNT signaling, mRNA metabolism and translation
signatures were present, consistent with qPCR and Western Blotting results. In
conclusion, these data demonstrate that the WNT signaling pathway, and in particular the
Wnt repressor HBP1, may play a critical role in pathogenesis of
Thesis (M.S.)--Tufts University, 2018.
Submitted to the Dept. of Pharmacology and Drug Development.
Advisors: Amy Yee, and John Castellot.
Committee: Eric Paulson, and Emmaneul Pothos.
Keyword: Molecular biology.read less