Role of sex hormones in lung cancer

Abstract

Lung cancer represents the world's leading cause of cancer deaths. Sex differences in the incidence and mortality rates for various types of lung cancers have been identified, but the biological and endocrine mechanisms implicated in these disparities have not yet been determined. While some cancers such as lung adenocarcinoma are more commonly found among women than men, others like squamous cell carcinoma display the opposite pattern or show no sex differences. Associations of tobacco product use rates, susceptibility to carcinogens, occupational exposures, and indoor and outdoor air pollution have also been linked to differential rates of lung cancer occurrence and mortality between sexes. While roles for sex hormones in other types of cancers affecting women or men have been identified and described, little is known about the influence of sex hormones in lung cancer. One potential mechanism identified to date is the synergism between estrogen and some tobacco compounds, and oncogene mutations, in inducing the expression of metabolic enzymes, leading to enhanced formation of reactive oxygen species and DNA adducts, and subsequent lung carcinogenesis. In this review, we present the literature available regarding sex differences in cancer rates, associations of male and female sex hormones with lung cancer, the influence of exogenous hormone therapy in women, and potential mechanisms mediated by male and female sex hormone receptors in lung carcinogenesis. The influence of biological sex on lung disease has recently been established, thus new research incorporating this variable will shed light on the mechanisms behind the observed disparities in lung cancer rates, and potentially lead to the development of new therapeutics to treat this devastating disease.

Keywords: Lung; cancer; carcinogenesis; estrogen receptors; sex differences; sex hormones.

Figure 1.

Estimated lung cancer statistics in the U.S. (2021). The estimated rates of lung cancer in the United States for 2021 are: (1) 235,760 new cases, including 119,100 in men and 116,660 in women. (2) The risk to develop lung cancer in one’s lifetime is about 1 in 15 for men and 1 in 17 for women. (3) About 69,410 yearly deaths from lung cancer are men, and 62,470 are women. (4) On average, 14.4% and 11.7% of men and women are daily tobacco users, respectively. (A color version of this figure is available in the online journal.)

Figure 2.

Role of smoking, air pollution, and estrogen in carcinogenesis. Exposure to tobacco smoke and/or environmental toxins leads to the uptake of carcinogens that are metabolized by lung cells. The estrogen metabolizing enzyme CYP1B1 is upregulated by tobacco carcinogens and estrogens, resulting in increased levels of carcinogenic derivatives of estrogen. CYP1B1 also metabolizes polycyclic aromatic hydrocarbons (PAH) resulting in PAH-DNA adduct formation. Unrepaired DNA adducts and inefficient DNA repair can result in DNA miscoding and mutations, leading to uncontrolled cell growth and lung neoplasia. (A color version of this figure is available in the online journal.)

Figure 3.

Estrogen/estrogen receptor signaling in lung carcinogenesis. Estrogen receptor β is expressed in cytoplasm, nucleus, mitochondria, and plasma membrane of lung cancer cells. ERβ activates the MAPK, cAMP, and AKT signaling mechanisms via the non-canonical (or non-genomic) pathway. Briefly, the E2/ER complexes translocate to the nucleus where they bind to estrogen response elements (ERE) to induce gene expression. Some of the genes regulated by ER and involved in lung cancer can promote apoptosis, metastasis, mitochondrial biogenesis, proliferation aromatase (ARO) mechanism, cell cycle progression (CXCL2), and angiogenesis (VEGF). (A color version of this figure is available in the online journal.) AKT: AKT serine/threonine kinase 1; cAMP: cellular levels of cyclic AMP; CREB: cAMP-response element binding protein; CXCL2: C-X-C chemokine ligand 2; CXCR4: C-X-C chemokine receptor type 4; E: estrogen; ERβ: estrogen receptor β; ERE: estrogen response elements; IKKs: IκB kinase; MAPK: mitogen-activated protein kinases; MEK: mitogen-activated protein kinase kinase; mERs: membrane estrogen receptors; NFκB: nuclear factor kappa-light-chain-enhancer of activated B cells; PI3K: phosphoinositide-3 kinase; PKA: protein kinase A; RAF: serine/threonine (S/T) kinase; RAS: guanine triphosphatase.

Figure 4.

Progesterone/progesterone receptor signaling in lung cancer. The growth factor receptor signaling is stimulated by its ligands (e.g. EGF, IFG-1, HRG), resulting in the activation of MAPK-related pathways and the subsequent stimulation of both (1) the ligand independent receptor activation and (2) the AKT/mTOR pathway, which increases and suppresses PR expression, respectively. In addition, estrogen and progesterone promote VEGF in lung cancer. (A color version of this figure is available in the online journal.) AKT: AKT Serine/Threonine Kinase 1; E: estrogen; EGF: epidermal growth factor; ERβ: estrogen receptor β; GFR: growth factor receptor; HRG: histidine rich glycoprotein; IGF-1: insulin-like growth factor 1; MAPK: mitogen-activated protein kinases; mTOR: mechanistic target of rapamycin; P: progesterone; PI3K: phosphoinositide-3 kinase; PR: progesterone receptor; PRE: progesterone response elements; VEGF: vascular endothelial growth factor.

Figure 5.

Androgens in lung cancer. Androgen receptor signaling induces cyclin D1 expression, tumor growth, and macrophage M2 polarization. There is also evidence that miR-224-5p negatively targets AR causing a decrease in tumor incidence and growth. (A color version of this figure is available in the online journal.) AR: androgen receptor; M2: Macrophage M2 polarization; T: testosterone.