Abstract
A higher incidence of colorectal cancer (CRC) is found in males compared to females. Young women (18–44 years) with CRC have a better survival outcome compared to men of the same age or compared to older women (over 50 years), indicating a global incidence of sexual dimorphism in CRC rates and survival. This suggests a protective role for the sex steroid hormone estrogen in CRC development. Key proliferative pathways in CRC tumorigenesis exhibit sexual dimorphism, which confer better survival in females through estrogen regulated genes and cell signaling. Estrogen regulates the activity of a class of Kv channels (KCNQ1:KCNE3), which control fundamental ion transport functions of the colon and epithelial mesenchymal transition through bi-directional interactions with the Wnt/β-catenin signalling pathway. Estrogen also modulates CRC proliferative responses in hypoxia via the novel membrane estrogen receptor GPER and HIF1A and VEGF signaling. Here we critically review recent clinical and molecular insights into sexual dimorphism of CRC biology modulated by the tumor microenvironment, estrogen, Wnt/β-catenin signalling, ion channels, and X-linked genes.
Highlights
When describing sex differences in cancer it is important to discriminate between sexual dimorphism and gender differences
Since the expression of these ER receptor subtypes is lost in colorectal cancer (CRC) tumor progression, it remains to be determined if estrogen and GPER can modulate sexual dimorphism in CRC cell survival through metabolic reprogramming under hypoxic conditions
It is interesting to note that the expression of all of the major ion transporters involved in colonic transepithelial Cl- secretion show sexual dimorphism and are modulated by estrogen and the estrous cycle in the female [170, 175], including CFTR a known tumor suppressor [190]
Summary
When describing sex differences in cancer it is important to discriminate between sexual dimorphism (biological differences in hormones and genes) and gender differences (nonbiological differences in societal attitudes and behaviour). Studies of the effects of HRT on cancer progression in postmenopausal women attributed a protective role to female sex hormones and encouraged many researchers into the area [31]. Consistent with these observations, a recent study in postmenopausal women in Japan [52] including 185 CRC patients and 361 controls, showed that higher testosterone levels were significantly associated with CRC risk (odds ratio 2.1 [95% CI, 1.11–3.99]).
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