WNT4 Balances Development vs Disease in Gynecologic Tissues and Women's Health

Abstract

The WNT family of proteins is crucial in numerous developmental pathways and tissue homeostasis. WNT4, in particular, is uniquely implicated in the development of the female phenotype in the fetus, and in the maintenance of müllerian and reproductive tissues. WNT4 dysfunction or dysregulation can drive sex-reversal syndromes, highlighting the key role of WNT4 in sex determination. WNT4 is also critical in gynecologic pathologies later in life, including several cancers, uterine fibroids, endometriosis, and infertility. The role of WNT4 in normal decidualization, implantation, and gestation is being increasingly appreciated, while aberrant activation of WNT4 signaling is being linked both to gynecologic and breast cancers. Notably, single-nucleotide polymorphisms (SNPs) at the WNT4 gene locus are strongly associated with these pathologies and may functionally link estrogen and estrogen receptor signaling to upregulation and activation of WNT4 signaling. Importantly, in each of these developmental and disease states, WNT4 gene expression and downstream WNT4 signaling are regulated and executed by myriad tissue-specific pathways. Here, we review the roles of WNT4 in women's health with a focus on sex development, and gynecologic and breast pathologies, and our understanding of how WNT4 signaling is controlled in these contexts. Defining WNT4 functions provides a unique opportunity to link sex-specific signaling pathways to women's health and disease.

Keywords: WNT4; Wnt signaling; breast cancer; estrogen; gynecologic cancer; invasive lobular carcinoma; müllerian tissues; organogenesis; ovarian cancer; reproduction; sex differentiation.

Figure 1.

Single-nucleotide polymorphisms (SNPs) at the WNT4 locus are associated with gynecologic pathologies. A, Map of index SNPs identified in primary genome-wide association studies and meta-analyses. B, Conditions and associated index SNPs. Studies listed correspond to (9), (14), and (42-62).

Figure 2.

WNT4 signaling pathways in uterine development and pregnancy. Details described in text. Transcription factors shown in purple text. Boxes denote key upstream regulatory factors that are “entry points” into the pathway.

Figure 3.

WNT4 signaling pathways in gynecologic pathologies. Details are described in the text. Transcription factors shown in purple text. Boxes denote key upstream factors that are critical in pathogenesis. Solid vs dashed lines represent transcriptional vs signaling effects, as in Fig. 2. The mechanisms by which WNT4 controls PI3K signaling in ovarian cancer are unknown, denoted by “?”.

Figure 4.

Intracellular WNT4 signaling. A, Wnt peptides are typically secreted via PORCN/Wntless (WLS) activity, but WNT4 can signal independent of secretion as a soluble, intracellular protein via receptor proteins to be identified. B, In invasive lobular carcinoma (ILC) cells, intracellular WNT4 signaling regulates mammalian target of rapamycin (mTOR) signaling via downstream S6 kinase, and also regulates cellular metabolism via control of mitochondrial dynamics.