Abstract 5256: Gender bias in rat models of colorectal cancer is owing to male hormone promotion, not female hormone protection

Abstract

Abstract Several large human colonoscopy screening cohort studies have found a significant sex and age-specific prevalence of advanced adenomas and colorectal cancer in males, with females showing a delayed onset and decreased incidence of advanced lesions. It has been postulated that women are protected from colorectal cancer owing to a protective effect of estrogen and progesterone, or that males are exposed to higher levels of environmental toxins. We find in both a genetic and a carcinogen-induced model of colorectal cancer in rats that male hormones are responsible for the male-specific enhancement of colon cancer. We have reported that the Polyposis in the rat colon (Pirc) rat shows a strong gender bias, with females having a later onset and reduced tumor burden compared to males. We have next investigated the role of hormones through ovariectomy and hormone replacement in female rats. F344-Pirc rat litters were divided and either underwent surgical ovariectomy or sham ovariectomy between 35 and 40 days of age. At the time of surgery, females received subcutaneous slow release (90 day) pellets with the following treatments: placebo; 17-beta estradiol (E2); medroxypregesterone (MPA); or a combination of E2 and MPA, renewed after 90 days, and sacrificed 180 days post ovariectomy. The controls were cohorts of females that did not receive surgical treatment (n=10), and sham ovariectomized females (n=10). Females that underwent ovariectomy and received either E2 (n=10) or the combination of E2 and MPA (n=10) had reduced body weight and were observed to be much leaner than animals treated with MPA alone (n=10, p=0.006) or placebo (n=8, p=0.005). Importantly, tumor multiplicities did not significantly differ among all female groups, but were significantly lower than those observed in intact males (n=32, mean 39.4, p=4.7e-14). We postulated that the difference of tumor susceptibility between sexes is due to the effect of male hormones. At weaning (30-35 days) half of the F344-Pirc males underwent orchidectomy. Males that underwent castration (n=16) had a significantly lower tumor multiplicity (mean=16.9) compared to all other males (n=32, mean= 39.4, p=1.3e-6). Males that underwent castration were indisguishable from all Pirc female cohorts, treated or not, strongly suggesting that male gonadal hormones are the significant hormones controlling the multiplicity of colonic adenomas. To determine if this response was specific to our genetic model, cohorts of F344 male rats either underwent orchidectomy or sham operation, and were then treated with the carcinogen azoxymethane. The orchidectomized cohort had a significantly lower number of aberrant crypt foci compared to the sham treated males (p=0.01). We are testing, through DHT replacement in the Pirc rat, whether testosterone is directly promoting the earlier onset and increased severity of colorectal cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5256. doi:1538-7445.AM2012-5256