Authors' Affiliations: USC Norris Comprehensive Cancer Center, Los Angeles; and Azusa Pacific University, Azusa, California.
Clin Cancer Res. 2013 Nov 1;19(21):5842-8. doi: 10.1158/1078-0432.CCR-13-0325. Epub 2013 Aug 21.
Worldwide, colorectal cancer has a higher incidence rate in men than in women, suggesting a protective role for sex hormones in the development of the disease. Preclinical data support a role for estrogen and its receptors in the initiation and progression of colorectal cancer and establishes that protective effects of estrogen are exerted through ERβ. Hormone replacement therapy (HRT) in postmenopausal women as well as consumption of soy reduces the incidence of colorectal cancer. In the Women's Health Initiative trial, use of HRT in postmenopausal women reduced the risk of colon cancer by 56% [95% confidence interval (CI), 0.38-0.81; P = 0.003]. A recent meta-analysis showed that in women, consumption of soy reduced the risk of colon cancer by 21% (95% CI, 0.03-0.35; P = 0.026). In this review, using the preclinical data, we translate the findings in the clinical trials and observational studies to define the role of estrogen in the prevention of colorectal cancer. We hypothesize that sometime during the tumorigenesis process ERβ expression in colonocytes is lost and the estrogen ligand, HRT, or soy products, exerts its effects through preventing this loss. Thus, in the adenoma-to-carcinoma continuum, timing of HRT is a significant determinant of the observed benefit from this intervention. We further argue that the protective effects of estrogen are limited to certain molecular subtypes. Successful development of estrogen modulators for prevention of colorectal cancer depends on identification of susceptible colorectal cancer population(s). Thus, research to better understand the estrogen pathway is fundamental for clinical delivery of these agents.
在全球范围内，男性结直肠癌的发病率高于女性，这表明性激素在该疾病的发展中起保护作用。临床前数据支持雌激素及其受体在结直肠癌的发生和发展中起作用，并确定雌激素的保护作用是通过 ERβ 发挥的。绝经后妇女的激素替代疗法（HRT）以及大豆的摄入都降低了结直肠癌的发病率。在妇女健康倡议试验中，绝经后妇女使用 HRT 使结肠癌的风险降低了 56%[95%置信区间（CI），0.38-0.81；P = 0.003]。最近的一项荟萃分析表明，在女性中，大豆的摄入使结肠癌的风险降低了 21%（95%CI，0.03-0.35；P = 0.026）。在这篇综述中，我们利用临床前数据，将临床试验和观察性研究的发现转化为雌激素在预防结直肠癌中的作用。我们假设，在肿瘤发生过程中的某个时间，结肠细胞中的 ERβ 表达丢失，雌激素配体、HRT 或大豆制品通过防止这种丢失来发挥作用。因此，在腺瘤-癌连续体中，HRT 的时间是观察到这种干预益处的重要决定因素。我们进一步认为，雌激素的保护作用仅限于某些分子亚型。成功开发用于预防结直肠癌的雌激素调节剂取决于确定易患结直肠癌的人群。因此，为了更好地了解雌激素途径而进行的研究对于这些药物的临床应用至关重要。
