Citation: Durovski, D.; Jankovic, M.; Prekovic, S. Insights into Androgen Receptor Action in Lung Cancer. Endocrines 2023, 4, 269–280. https:// doi.org/10.3390/endocrines4020022 Academic Editor: Marco Falasca Received: 10 January 2023 Revised: 28 February 2023 Accepted: 28 March 2023 Published: 3 April 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Review Insights into Androgen Receptor Action in Lung Cancer Darko Durovski 1 , Milica Jankovic 2 and Stefan Prekovic 3, * 1 Leiden University Medical Center, 2333 ZA Leiden, The Netherlands 2 Department of Molecular Biology and Endocrinology, “Vinˇ ca” Institute of Nuclear Sciences, University of Belgrade, 11000 Belgrade, Serbia 3 Center for Molecular Medicine, University Medical Center Utrecht, 3584 CG Utrecht, The Netherlands * Correspondence: s.prekovic@umcutrecht.nl; Tel.: +31-655576959 Abstract: Sex hormones and their receptors play a crucial role in human sexual dimorphism and have been traditionally associated with hormone-dependent cancers like breast, prostate, and endometrial cancer. However, recent research has broadened our understanding by revealing connections with other types of cancers, such as lung cancer, where the androgen receptor has been found to be particularly significant. This review aims to explore the molecular mechanisms of androgen action in lung cancer pathogenesis and progression, highlighting the potential of inhibiting the androgen receptor signaling pathway as a therapeutic strategy for lung cancer treatment. Keywords: androgens; nuclear receptors; lung cancer 1. Introduction Lung cancer stands as the foremost cause of cancer-related mortality globally, annually causing nearly 1.8 million fatalities [1], with an estimated 127,000 deaths projected for the year 2023 in the United States by the American Cancer Society [2]. This disease is often asymptomatic, diagnosed at a late stage [3], and characterized by the lowest 5-year relative survival rate out of all cancer types [4]. Importantly, reliable biomarkers for early stages of lung cancer are still missing [5]. Different types of lung cancer exist and can broadly be divided into two major groups: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). The former type, which includes lung squamous cell carcinoma, lung small cell carcinoma, and lung adenocarcinoma, accounts for 80% of all lung cancer cases [4]. The most common subtype of NSCLC is adenocarcinoma, which represents the most prevalent subtype among non-smokers [6]. SCLC is usually diagnosed in patients with smoking history and older than the age of 70, with a major fraction of these patients succumbing to the consequences of the disease rapidly [7]. The main risk factor associated with lung cancer development is tobacco smoke, which contains numerous carcinogens that can cause DNA damage [3]. Smoking-related DNA damage can lead to mutations in tumor suppressor genes, such as p53, which normally help prevent the accumulation of DNA damage and, thus, prevent the development of cancer. In addition to smoking, environmental and/or occupational exposure to pollution, chronic lung disease, lifestyle factors, and genetic factors may also contribute to the development of lung cancer [3]. Mutations in EGFR, KRAS, BRAF, and HER2 have been identified as drivers of lung cancer [8], and the fusion of ALK, ROS1, and RET protein tyrosine kinase oncogenes with multiple partner genes has been linked to the development and progression of non- small cell lung cancer, particularly lung adenocarcinoma [9]. Recent studies have also suggested that sex hormone receptors and their corresponding ligands may play a role in the pathogenesis of lung cancer [10]. Sex hormone receptors, including androgen receptor (AR), estrogen receptors (ER) α and β, as well as progesterone receptor (PR)-A and PR-B, belong to the steroid receptor subgroup of the nuclear receptor (NR) superfamily, which consists of 48 members of transcription factors (TFs) with roles in metabolism, reproduction, Endocrines 2023, 4, 269–280. https://doi.org/10.3390/endocrines4020022 https://www.mdpi.com/journal/endocrines