Sex Modulates Intestinal Transformation by the Tumor‐Suppressor GCC

Abstract

There is an established relationship between sex and colorectal tumorigenesis, and the annual age-adjusted incidence of colorectal cancer in the United States is higher in men than in women. In addition, there are sex differences regarding the anatomic location and clinicopathological characteristics of tumors. Moreover, hormone replacement therapy (HRT) in postmenopausal women reduces the risk of colorectal cancer by 30–40%. However, while ovarian hormones mitigate colorectal cancer risk by modifying genetic and environmental determinants, the precise mechanisms remain undefined. In that regard, the most commonly lost gene products in intestinal neoplasia include guanylin and uroguanylin, paracrine hormones for guanylyl cyclase C (GCC), an emergent tumor-suppressor regulating crypt hyperplasia, proliferation, and the cell cycle. Of note, the molecular intersection between intestinal paracrine and systemic sex hormones opposing intestinal neoplasia has not been explored. Here, the impact of GCC on tumorigenesis was examined in mice carrying mutations in Apc (Apc Min/+) or exposed to azoxymethane (AOM), models of genetic and chemical intestinal carcinogenesis. Proliferation of intestinal epithelial cells was quantified employing molecular markers of the cell cycle. While elimination of GCC expression increased tumor burden in Apc Min/+ and AOM-treated mice, females exhibited only approximately 50% of the burden observed in males. Of note, elimination of GCC expression promoted epithelial cell proliferation in males but not in females. These observations reveal an intersection between sex and the GCC-based paracrine hormone axis, converging at restriction of crypt cell proliferation. They suggest that the invariable loss of guanylin and uroguanylin and the resultant downstream effects on tumorigenesis are mitigated by sex. In the context of the established association between HRT, menopause, and the risk of colon cancer, and the inhibition by estrogen of cell cycle regulators, it is presumed that hormonal components of the ovarian axis mediate these protective effects. This previously unappreciated synergy between sex and the GCC signaling axis suggests a unique opportunity for cancer prevention and treatment. Indeed, while expression of guanylin and uroguanylin is invariably lost early along the continuum of neoplastic transformation, GCC is universally overexpressed by human colorectal tumors. In the context of the standard of care in which hormone deficiencies are treated by replacement, the present observations underscore the potential for combining systemic sex and GCC paracrine hormone supplementation for targeted prevention and therapy in colorectal cancer.