Colorectal Cancer Risk Associated with Hormone Use Varies by Expression of Estrogen Receptor-β

Abstract

The risk of colorectal cancer is reduced among users of oral contraceptives or menopausal hormone therapy, but associations with reproductive characteristics that are markers of a woman's endogenous hormone milieu have not been consistently observed. To help understand possible mechanisms through which exogenous and endogenous hormonal exposures are involved in colorectal cancer, we assessed the risk of these malignancies according to tumor expression of estrogen receptor-b (ESR2). In a population-based study of postmenopausal women (503 cases and 721 controls matched for sex and age), immunohistochemical expression of ESR2 was determined in 445 cases of incident colorectal cancer. Unconditional logistic regression was used in case-case analyses to assess heterogeneity between risk associations according to ESR2 status and in case-control analyses to estimate associations separately for ESR2-negative and ESR2-positive tumors. For ESR2-positive tumors but not ESR2-negative tumors, colorectal cancer risk significantly decreased with duration of oral contraceptive use [per five-year increments OR ESR2-positive, 0.87, 95% confidence interval (CI), 0.77-0.99; OR ESR2-negative, 1.02, 95% CI, 0.91-1.15; P heterogeneity ¼ 0.07] and with duration of menopausal hormone therapy use (per five-year increments OR ESR2-positive, 0.84, 95% CI, 0.74-0.95; OR ESR2-negative, 0.94, 95% CI 0.84-1.05; P heterogeneity ¼ 0.06). Significant heterogeneity according to ESR2 expression was found for the association with current use of menopausal hormone therapy (<0.5 years ago; P heterogeneity ¼ 0.023) but not for associations with reproductive factors. In conclusion, our results suggest that hormone use decreases risk for ESR2-positive but not ESR2-negative colorectal cancer. Cancer Res; 73(11); 3306-15. Ó2013 AACR.

Nonlinear reduction in risk for colorectal cancer by oral contraceptive use: a meta-analysis of epidemiological studies

“…The summary RRs for the longest versus shortest were 0.85 (95 % CI 0.74-0.97), almost identical to the results of the primary analyses. Meanwhile, exclusion of two studies [27,38] in which RRs and 95 % CI were not reported but calculated from raw data or five studies [24,38,39,42] not adjusted for any confounders or two studies [22,23] reporting the risk estimates with CRC mortality, the results were similar to the original analysis (data not shown).…”

“…We extracted the RRs that reflected the greatest degree of control for potential confounders for use in the main analyses. If no estimate was presented in a given study, we calculated it and its 95 % CI according to the raw data presented in the article [27,38]. Similar to our previous studies [44,45], we did not assess study quality using a quality score, but investigated whether specific study characteristics, such as study design and adjustment for confounders, which are indicators of study quality, influenced the results in subgroup analyses.…”

“…We identified twelve cohort studies [16][17][18][19][20][21][22][23][24][25][26]43] and seventeen case-control studies [27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42] that presented results on OC use and CRC risk. Table 1 summarizes the characteristics of these included studies.…”

“…The median duration of follow-up was 11 years. Of the seventeen case-control studies, nine were from North America [29-31, 34, 35, 37, 39, 41, 42], four from Europe [27,32,33,36], two from Australia [38,40], and one each from China [42] and Africa [28]. Control subjects were drawn from the general population in thirteen studies [27, 29-31, 34-38, 40-42], hospitals in three studies [28,32,33], and unknown population in one study [39].…”

Genistein induces activation of the mitochondrial apoptosis pathway by inhibiting phosphorylation of Akt in colorectal cancer cells

“…However, the use of exogenous hormones is associated with a decreased risk for estrogen receptor-b-positive (ERb-positive), but not estrogen receptor-b-negative (ERb-negative) colorectal cancer (Rudolph et al, 2013). Although ERa and ERb are the two known subtypes through which estrogens exert their effects on various tissues, ERb is the predominant estrogen receptor subtype in the human colon and decreased levels of ERb are associated with colonic tumorigenesis (Campbell-Thompson et al, 2001;Pampaloni et al, 2014).…”