It is still debatable how sex hormones can exhibit antitumor effects in CRC since they act as carcinogenic in other tissues, but based on existent information, this protection can be attributable to the roles that estrogen receptors—ER (mainly ERβ)—play in multiple processes involved in CRC development and progression, such as tumor microenvironment (hypoxia, cellular metabolism, drug metabolism, angiogenesis, gut microbiome, etc.), ion channel function, immunity, apoptosis of cancer cells, and cell cycle regulation [5,6]. The gene discussed is ESR1; the disease is neoplasm.