Carcinogenesis is associated with sex-biased tissue environments and imbalances between estrogen receptor alpha and thyroid hormone receptors

There is extensive evidence of sex differences in the susceptibility and prognosis of non-reproductive cancers. In addition to external factors, biological sex bias (e.g., sex chromosomes, hormones, and immune function) is suspected to function as a selective pressure that influences the evolutionary process of carcinogenesis. However, there remains a lack of clarity concerning the extent of the effect of sex bias on carcinogenesis, as well as the underlying mechanism. In this study, we show that tissue sex bias, correlated to gonadotropin-releasing hormone, varies among tissues and is associated with two distinct age-specific patterns of cancer incidence: parallel and nonparallel. Additionally, we reveal that imbalances in estrogen receptor alpha and thyroid hormone receptors are associated with levels of hypoxia-inducible factors, which have three phases (hypoxia, hyperoxia, and “chaotic-oxia”) that exist in most cancers and are linked to specific cancer subtypes, including cancers with microsatellites, the CpG island methylator phenotype, or hypermethylation. Our results suggest that sex-biased tissue environments and hormonal imbalances may influence the incidence pattern and direction of carcinogenesis, emphasizing the importance of maintaining hormonal homeostasis for cancer prevention and providing insights toward improving therapies for cancer types with hormonal imbalances. Plain English summary Sex bias has been long observed in cancer susceptibility and prognosis. Hormone difference between the two sexes was believed to play a role. However, the mechanism is still largely unknown. Our study has shown that the activity of one hormone secreted from pituitary, namely gonadotropin-releasing hormone, are correlated to sex-biased tissue environment, which was speculated to influence incidence patterns of carcinogenesis. Furthermore, hormonal imbalance, particularly imbalance in receptors of estrogen and thyroid hormone, which is associated with specific cancer subtypes, was speculated to influence the direction of carcinogenesis. Highlights ### Competing Interest Statement The authors have declared no competing interest.