Testosterone and Androgen Receptor in Cancers with Significant Sex Dimorphism in Incidence Rates and Survival

Abstract

Several major cancer types exhibit significant sex dimorphism in incidence and survival. Whether and how sex as a biological factor impacts tumorigenesis, progression, and survival warrants full investigation, as such knowledge may lead to novel, precise prevention and treatment strategies. We reviewed epidemiological and molecular data on sex differences in cancers of the esophagus, bladder, head and neck, lung, liver, kidney, stomach, and skin melanoma, as well as the potential role of androgens and androgen receptor (AR) activity in these cancers. The potential molecular mechanisms are briefly discussed. Elevated testosterone (T) levels seemed to be associated with increased liver cancer and cutaneous melanoma incidences, and with reduced esophageal cancer risk. AR activity does not always correlate with T levels in tumorigenesis and progression. Higher AR expressions are associated with poorer survival in ESCC, whereas the role of AR in the survival of HNSCC and melanoma patients is inconsistent. The molecular impact of AR in liver cancer, kidney cancer, melanoma, and lung cancer is controversial. However, AR is likely to promote tumor growth and/or progression in esophagus, bladder, head and neck, and stomach cancers, and thus is associated with poor survival. Patients diagnosed with a tumor in this latter group could potentially benefit from therapeutic approaches targeting AR. Overall, the research on sex hormone androgens and AR in these cancers is limited. Further research is needed to determine a possible U-shaped relationship of T with cancer risk, and to decipher the role of testosterone and AR in some of these tumors to facilitate our understanding of sex dimorphism and to explore novel T/AR-based treatment options.

Keywords: androgen receptor; cancer; sex dimorphism; testosterone.

Figure 1

Illustration of U-shaped effects of T/AR axis and their potential pathways.

Figure 2

A brief summary of AR signaling. The diagram illustrates the mechanisms of androgen receptor (AR) signaling in response to androgen. In the genomic pathway, androgen diffuses across the cell membrane. Androgen binds to cytoplasmic AR, which is maintained in an inactive conformation by chaperone proteins. Ligand binding induces AR activation, chaperone dissociation, and subsequent nuclear translocation. Within the nucleus, AR-Androgen complexes bind to androgen response elements (AREs) on DNA, recruiting co-regulatory proteins to modulate transcription of target genes.

Figure 3

AR mRNA expression in normal (A) and normal vs. tumor tissues. The gene expression in normal tissue was based on GTEx data (Genotype-Tissue Expression, with all tissues included), the normal vs. tumor expression was based on an integrated database which included TCGA (The Cancer Genome Atlas), GTEx, TARGET (Therapeutically Applicable Research to Generate Effective Treatments), and NCBI GEO data [33]. The y-axis in (B) is batch-adjusted and normalized counts. All comparisons showed significant differences (α < 0.05).

Figure 4

Sex disparities in age-adjusted cancer incidence rates across multiple cancer types (SEER 17 data, 2000–2022). Trends in age-adjusted cancer incidence rates (per 100,000 person-years) from 2000 to 2022 for males (orange), females (red), and all (blue) patients across 8 cancer types. Data were obtained from the SEER Research Limited-Field Database (17 registries; November 2024 submission). Rates were age-adjusted to the 2000 U.S. standard population.