The Sex Bias of Cancer

Sex hormones are relevant modulators of cancer onset and progression in nonreproductive organs. Sex hormone receptors are as important as hormone levels in cancer progression. Depending on the organ, sex hormones may have opposite effects on cancer progression. Differences in cancer onset and progression between men and women deserve more profound investigation. In hormone-dependent organs, sex hormones and dysregulated hormone signaling have well-documented roles in cancers of the breast and female reproductive organs including endometrium and ovary, as well as in prostate and testicular cancers in males. Strikingly, epidemiological data highlight significant differences between the sexes in the incidence of various cancers in nonreproductive organs, where the role of sex hormones has been less well studied. In an era when personalized medicine is gaining recognition, understanding the molecular, cellular, and biological differences between men and women is timely for developing more appropriate therapeutic interventions according to gender. We review evidence that sex hormones also shape many of the dysregulated cellular and molecular pathways that lead to cell proliferation and cancer in nonreproductive organs. In hormone-dependent organs, sex hormones and dysregulated hormone signaling have well-documented roles in cancers of the breast and female reproductive organs including endometrium and ovary, as well as in prostate and testicular cancers in males. Strikingly, epidemiological data highlight significant differences between the sexes in the incidence of various cancers in nonreproductive organs, where the role of sex hormones has been less well studied. In an era when personalized medicine is gaining recognition, understanding the molecular, cellular, and biological differences between men and women is timely for developing more appropriate therapeutic interventions according to gender. We review evidence that sex hormones also shape many of the dysregulated cellular and molecular pathways that lead to cell proliferation and cancer in nonreproductive organs. a nuclear receptor that is activated by androgen binding in the cytoplasm and then translocates to the nucleus. The AR is a DNA-binding transcription factor that regulates the expression of genes that are crucial for the development and maintenance of the male sexual phenotype and skeletal integrity, and for female sexual, somatic, and behavioral functions. an endogenous androgen sex steroid hormone whose formation from testosterone is catalyzed by 5α-reductase. It is the most potent known endogenous ligand of AR. Unlike other androgens, DHT cannot be converted by the enzyme aromatase into estrogen, and is thus frequently used to distinguish between the effects of testosterone and those caused by testosterone conversion to estradiol. the major female sex hormone that modulates the activity of target tissues principally by interacting with the two nuclear receptors, ERα and ERβ. E2 is involved in the regulation of the male and female reproductive systems, in neuroprotection of the nervous system, and regulates other tissues including bone, skin, liver, and blood vessels. E2 has also been tied to cancer development and progression. steroid hormone receptors that are important in sexual maturation and gestation. There are two classes of ER: nuclear estrogen receptors (ERα and ERβ), and membrane estrogen receptors (GPER, ER-X, and Gq-mER). In the cytoplasm, once activated by 17β-estradiol, nuclear ERs translocate to the nucleus and bind to DNA to regulate the activity of different genes. a signal transduction pathway that promotes survival and growth in response to extracellular signals. Impairment of PI3K/Akt pathway has been linked to a range of diseases, such as cancer, where its upregulation promotes cell survival, migration, and angiogenesis, cell-cycle progression, and increased glucose metabolism. an endogenous steroid and progestogen sex hormone that is involved in the menstrual cycle, pregnancy, and embryogenesis. P4 has a variety of important functions in the body and is also a crucial metabolic intermediate in the production of other endogenous steroids It also plays an important role in brain function as a neurosteroid. a nuclear receptor that is activated by P4. In humans, PR has two isoforms, PR-A and PR-B. Once activated by progesterone binding, the complex enters the nucleus, binds to DNA, and regulates the transcription of target genes. the primary male sex hormone and anabolic steroid. In males, it plays a key role in the development of reproductive tissues as well promoting secondary sexual characteristics. It is also involved in health and well-being, as well as in preventing osteoporosis. It exerts its action by activating AR. Free testosterone is transported into the cytoplasm of target tissue cells or can be reduced to 5α-dihydrotestosterone (DHT), which binds to AR more strongly than testosterone.