Androgen Receptor in Lung Development and Lung Cancer: History
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Subjects: Oncology
Contributor:
Darko Durovski
,
Milica Jankovic
,
Stefan Prekovic

Sex hormones (SHs) and their receptors (SHRs) play a crucial role in human sexual dimorphism and have been traditionally associated with hormone-dependent cancers like breast, prostate, and endometrial cancer. Research has broadened the understanding by revealing connections with other types of cancers, such as lung cancer (LC), where the androgen receptor (AR) plays a significant role. 

  • androgens
  • nuclear receptors
  • lung cancer
  • non-small cell lung cancer
  • testosterone
  • androgen receptor
  • sex-hormone receptors
  • gender-related cancers
  • sex steroid hormones in cancers

1. Introduction

Lung cancer (LC) is one of the leading causes of cancer-related mortality globally, annually causing nearly 1.8 million fatalities [1]. Due to its asymptomatic, stealthy course, LC is diagnosed at a late stage and has the lowest 5-year relative survival rate among all cancer types [2][3]. In relation to that, reliable biomarkers for early stages of LC are still missing [4]. LC types can be broadly divided into two major groups: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Further subgroups of NSCLC include lung squamous cell carcinoma, lung small cell carcinoma, and lung adenocarcinoma (LUAD), which together account for 80% of all LC cases [4]. The most common subtype of NSCLC is LUAD which is most prevalent among non-smokers [5]. SCLC is usually diagnosed in elderly patients (over 70 years old) with smoking history and it has a rapidly lethal outcome [6].
The main risk factor (RF) associated with LC development is smoking, as nicotine contains various DNA-damaging carcinogens [2]. DNA damage due to smoking can lead to mutations in tumor suppressor genes (TSGs), such as p53, whose normal function is to help prevent DNA damage accumulation, a protection mechanism against cancer development. Other RFs in LC development include environmental and/or occupational exposure to pollution, chronic lung disease, lifestyle factors, and genetic factors [2]. Mutations in EGFR, KRAS, BRAF, and HER2 have been identified as drivers of LC, 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 NSCLC, particularly LUAD [7][8]. Recent studies have also suggested that sex hormone receptors (SHRs) and their corresponding ligands may play a role in LC pathogenesis [9]. SHRs androgen receptor (AR), estrogen receptors (ER)-α and -β, and progesterone receptors (PR)-A and PR-B, belong to the steroid receptor subgroup of the nuclear receptor (NR) superfamily, a family of 48 members of transcription factors (TFs) with roles in metabolism, reproduction, inflammation, and development [10]. Dysregulation in the SH signaling pathway (SP) has been implicated in prostate, breast, and LC development [9].
Studies report higher LC incidence in female as opposed to male patients. However, despite frequent diagnosis at advanced stages, female patients tend to have better 5-year survival outcomes and a better prognosis compared to male patients [11]. Additionally, there are differences in subtype prevalence, with LUAD and bronchioloalveolar carcinoma (BAC) being diagnosed more often in female patients, even after accounting for smoking status (SS) as a RF [12].

2. Androgens and the Androgen Receptor

Sex hormones (SHs) are synthesized in the gonads, adrenal glands, or locally in other tissues [12]. Cholesterol is the precursor to all steroid hormones, including glucocorticoids and mineralocorticoids. Essential for the SH SP, the enzyme P450-linked side chain cleaving enzyme, converts cholesterol into pregnenolone, which acts as a precursor for estrogen and androgen. Pregnenolone is converted to less potent androgens, which ultimately serve as backbones for testosterone (T) biosynthesis. Most of the synthesized T is bound to albumin and sex-binding hormone globulin (SBHG), and only 2–3% circulates freely in the serum as biologically active [13][14]. In particular tissues, T can be converted to a more potent dihydrotestosterone (DHT) hormone by the enzyme 5-α reductase [15]. Three isoenzymes of 5-α reductase exist: types 1, 2, and 3 [13]. Type 3 was identified in both benign and malignant lung tissue and its overexpression was detected in LUAD samples [16].
Androgen receptor (AR) is a member of the nuclear receptor (NR) family that shares structural similarities with ERs, GRs and PRs. After androgens bind to AR, the receptor changes its confirmation and the protein translocates to the nucleus, where it binds to the specific DNA response elements known as hormone response elements (HREs), mostly found at enhancer regions, distal to AR target genes. After AR engages with HREs, nuclear proteins, such as co-activators and co-repressors, are recruited to ultimately influence transcriptional output of its target genes [17][18]. (Figure 1). This is the classical mode of action of AR. Additionally, androgens can induce rapid activation of other non-classical pathways in cells, including the MAPK pathway, PI3K/Akt pathway, and Src tyrosine kinase pathway [19].
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Figure 1. This scheme illustrates the intricate signaling mechanism of the androgen receptor and its corresponding gene/protein structure. Data from Protein Database (https://www.rcsb.org (accessed on 27 February 2023)); IDs 1R4I and 1T5Z.
AR has a multi-domain composition, consisting of three distinct functional units (Figure 1). These include an N-terminal transactivation domain (NTD), a DNA-binding domain (DBD), and a ligand-binding domain (LBD) [20]. The NTD houses an activation function (AF)-1 domain that works in tandem with co-regulatory proteins to modulate gene transcription. Meanwhile, the DBD is responsible for binding to specific DNA sequences, known as androgen response elements (AREs), which are strategically located in the promoter regions of target genes. Lastly, the LBD is composed of two critical components, the AF-2 domain and the ligand-binding pocket. The AF-2 domain interacts with co-regulatory proteins, whereas the ligand-binding pocket binds to androgens. Notably, the hinge region connects the DBD and LBD and is vital for AR stability and function [21].
AR is further characterized by multiple splice variants, including the well-known AR-V7. The constitutively active AR-V7 lacks the ligand-binding domain (LBD) and was linked to androgen deprivation therapy resistance in prostate cancer (PCa) patients [22]. Additionally, other splice variants, such as AR-V1, AR-V2, and AR-V3, could also play a role in the development and progression of PCa [23]. Furthermore, mutations in AR can affect its activity and are associated with various diseases, such as androgen insensitivity syndrome (AIS) and PCa [24]. These mutations can occur in different domains of the receptor, including the DNA-binding domain (DBD) and LBD. Mutations in the LBD can alter the specificity of ligand binding, enabling activation by other hormones, such as progesterone and estrogen [24].
The AR mediates effects of male SHs in reproductive and non-reproductive organ systems. Following its discovery in the 1960s, the expression of this receptor was demonstrated in several tissues, including bone, muscle, prostate, and adipose tissue [25]. Over the years, it was shown that AR role extends beyond sexual development, with its signaling contributing to various biological processes—including brain development, metabolism, and immune system [26]. Moreover, researchers demonstrated that AR plays a pivotal role in AIS, Kennedy’s disease and cancer [27][28]. In particular, in terms of cancer, AR is the critical driver of PCa; nonetheless, its dysregulation could contribute to bladder, kidney, breast, and liver cancer development [29][30].

3. Role of the Androgen Receptor in Lung Development

In addition to their role in sexual development, SHs play a role in lung development. Mammalian lung development occurs in five histologically distinct stages: embryonic, pseudoglandular, canalicular, saccular, and alveolar [31][32]. Transitions between stages are under multifunctional molecular control by growth factors (GFs), TFs, glucocorticoids, and SHs [31]. The fetal lung is exposed to circulating SHs produced by C19 steroid precursors in maternal and fetal adrenals. Moreover, in fetal lungs, SHs can be inactivated by specific enzymes, adding another layer of regulation [31]. Normal lung development differs between males and females, with maturation and surfactant production occurring earlier in the latter group [33][34].
Androgens can affect lung development differently, depending on the stage. They can act as positive regulators in the process of branching morphogenesis in early development and as negative regulators responsible for delay in male lung maturation in late stages (Figure 2) [31]. Branching morphogenesis occurs at week five of gestation, with all airway branching occurring by week 24 of fetal life; AR is predominantly expressed in epithelial cells found at budding sites during this process [35][36]. The expression of AR was shown in both murine and human type II pneumocytes and bronchial epithelium [37]. The negative influence of androgens on lung development was demonstrated in vivo, whereby male animals were found to have less developed lungs compared to their female counterparts [32]. Surfactant production in the fetal developing lung is under multifactorial and multihormonal control. Glucocorticoids and estrogens can accelerate the production of surfactant phospholipids and proteins, while androgens can inhibit it [37]. The inhibitory role of T and DHT on pulmonary surfactant production was shown in organ cultures and in vivo mouse and rabbit models, where the effects were attributed to hormone interactions with the AR found in lung fibroblasts and alveolar type II cells. [38] Despite the well-established role of AR in lung development, the precise role of AR in normal lung physiology remains uncertain and warrants further investigation.
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Figure 2. The scheme depicts the impact of androgens on lung development and function.

4. Androgens and the Androgen Receptor in Lung Cancer

4.1 Androgen Receptor Signaling in Lung Cancer

Both the functional AR protein and 5α-reductase were expressed in SCLC models [38]. AR expression was also demonstrated in NSCLC in cell lines and primary lung cancer material.[39] After this observation, studies have also demonstrated its presence in LC cell line models [40][41], while alterations were observed in 5% of LSC and AD, which further supports the view that the receptor plays a significant role in LC [42]. 

LC cell lines were also shown to express steroid-converting enzymes [38]. A549 cells expressed the enzyme 17β-hydroxysteroid dehydrogenase (HSD) type 5 and 3α-HSD type 3, which produce steroid precursors that can activate the AR; the latter enzyme was present in a low quantity, though the cells expressed AR at a high level [38]. SH-inactivating enzymes were also detected in LC cells, mouse and human fetal lung tissue. Low 17β-HSD catalyzes the conversion of 3α-adiol to DHT and androsterone to epi-androsterone, with its downregulation linked to poor patient prognosis in hepatocellular carcinoma and LUAD, where it was associated with poor clinicopathological features, such as tumor size, advanced tumor stage, low tumor differentiation and poor patient prognosis [39]. It reduces radioresistance in LC cells and suppresses proliferation, migration, invasion and epithelial-mesenchymal transition (EMT), with a potential mechanism including PTEN expression and inhibition of AKT phosphorylation [40].

Anrdogens influence cancer cells with T increasing protein synthesis rates, basal cell metabolism and energy [41]. AR in murine cells leads to upregulation of genes involved in oxygen transport and heme biosynthesis and negative regulation of genes involved in apoptosis, DNA repair and double-strand (ds) break repair (br) [41]. Research led to contrasting conclusions about the link between T and hormone-dependent cancer incidence [42].

Androgens also influence cellular processes and SPs in NSCLC. Androgen treatment changed the transcriptional landscape in murine lung tissue and human NSCLC cell lines; in A549 cell line models, it led to upregulation of genes involved in oxygen transport and utilization and downregulation of those in DNA repair and recombination [41]. AR SP modulation elucidated a crosstalk between AR and KRAS. AR cooperates with EGFR and Raf/MEK/ERK pathways in cellular processes such as differentiation, growth, chemotaxis and apoptosis [43]. AR knockdown (kd) in NSCLC cell lines led to inhibition of cell proliferation and achorage-independent growth in vitro [44][45]. AR suppression was also linked to the SPs affecting stemness and self-renewal [44].

EGFR was also involved in DHT-induced growth stimulation of A549 LC cells and LNCaP prostate tumor cells. DHT treatment led to CD1 upregulation and cell proliferation, both of which could be mitigated by selective inhibitors or kd of AR/EGFR. Cross-talk between AR and EGFR plays a role in the progression of PCa and LC through activation of mTOR/CD1 pathway [5].

T treatment in a female NZR-GD rat LC model resulted in enhanced lung tumor formation, while the same effects could not be observed in hepatocellular and kidney epithelial tumors [46]. Similar findings came from an AR knockout (ARKO) mouse model where it resulted in reduced tumor size compared to control NNK-BaP mice [45].

4.2. Androgen Receptor as an Important Factor in Lung Cancer Biology: Evidence from Clinical Studies

A cohort study investigating total blood T levels in 3635 community-dwelling elderly men found a positive link with LC risk [14]. Performing a liquid chromatography-mass spectrometry (LC-MS) study on the same sample, researchers found that an increase in total T, equivalent to 4.87 nmol/L, significantly increased the adjusted risk of LC (HR = 1.30, 95% CI 1.06–1.60; p = 0.012). For every 1 SD (0.73 nmol/l) increase in DHT, the adjusted risk of LC increased by 29% (HR = 1.29, 95% CI 1.08–1.54; p = 0.004).[47] Smoking was not a confounding factor in either study [14][47]. Contrastingly, one prospective cohort study of 291 male and 193 female participants found no association between plasma T levels and LC risk [42].

AR expression was investigated in primary LC tissues where intra-tumor AR expression was detected in a minor fraction of primary LC tissues (18/566 cases) [48]. An immunohistochemistry-based study found no association between AR expression and OS in 136 tissue samples from tumor bank patients [11]. There was a significant correlation with outcome and SHRs in 62 patients with advanced NSCLC. Intra-tumor presence of AR, ER-α,and PgR were correlated with outcomes in advanced NSCLC patients. Patients with nuclear and cytoplasmic AR expression exhibited longer survival when compared to those not expressing the protein (49 and 45 months, respectively, vs. 19 months) — although the number of patients demonstrating nuclear AR expression was relatively low (8/62) [49]. Cytoplasm and nucleus AR expression in tumor tissues from 335 patients revealed worse outcomes with respect to disease-specific survival compared to the rest of the cohort [50].

Mutation-profile examination in cell-free DNA in plasma samples of LC patients revealed the expression of the AR p.H875Y mutation previously found in PCa and BC and associated with activation by other steroid hormones. AR +/+ mutation samples showed a higher mutational burden compared to double negative samples. The exact functional relevance of mutation in lung carcinogenesis is yet to be investigated [51].

AR was not significantly associated with locoregional control, metastases-free survival and OS in stage II/III NSCLC tumors of RT-receiving patients in a study investigating SHR expression and said parameters [3]. 

4.3. Targeting of the Androgen Receptor Pathway 

Blocking the AR SP pharmacologically can be achieved by targeting AR or enzymes responsible for the conversion of steroid precursors into T or DHT [52]. CYP17A1 and 5-α reductase inhibitors can be used to block T-producing enzymes and prevent T conversion to DHT. Non-steroid anti-androgens can bind to AR and engage in competitive binding with T and DHT.[53] Steroidal anti-androgens can inhibit androgen action and luteinizing hormone (LH) secretion in a competitive manner, which can lead to decreased T production. Gonadotropin-releasing hormone (GnRH) agonists can downregulate GnRH Rs and decrease LH and T [12]. 

Pharmacological targeting of the AR SP in LC was investigated in NSCLC cell lines, where its inhibition was associated with radiosensitization [44]. The expression of miR-224-5p, an exosome-secreted microRNA was detected in cancer specimens. Its overexpression led to an acceleration through the cell cycle and inhibition of apoptosis, while its inhibition led to decreased proliferative and migratory capacity of two LC cell lines. In a tumor xenograft mouse model, injection of the miRNA-overexpressing cells led to growth increase and necrotic tissue appearance in the lungs, along with epithelial-to-mesenchymal transition (EMT) [54].

The effect of androgen pathway manipulation (APM) was investigated on survival in 3018 men diagnosed with LC; 339 individuals had used a form of APM prior to the study being conducted [12]. APM use in patients after LC diagnosis and before and after diagnosis led to better survival outcomes compared to patients with no APM use. Exposure to APM was associated with longer survival in early-stage disease and if treatment occurred after diagnosis. In late-stage disease, there was a significant effect in those exposed to APM after diagnosis (HR = 0.41, p = 0.02) and before and after diagnosis (HR = 0.54, p < 0.0001) [12].

A study investigated the effect of a proteasome-based system with proteolysis-targeting chimeras (PROTACs) in LC cell lines. PROTACS harness the ubiquitin-proteasome system to degrade target proteins. An enzalutamide-based PROTAC led to a dose-dependent reduction of viability in a LC cell line model [55]. A summary of the mechanisms in which the AR complex can modulate cellular processes related to LC is shown in Figure 3.

This scheme visually represents how active AR affects lung cancer, with red and blue outlines indicating positive and negative regulation, respectively.

5. Discussion 

There are several points to consider when analyzing the role SHs and their receptors play in LC. Two confounding factors in clinical studies of LC patients that are inconsistently reported are patient SS and menopausal status. Nicotine can act as a double confounder as it increases unbound T in healthy men and independently increases LC incidence [14][56]. Another confounding factor can be menopausal status in female patients as NRs can crosstalk; though in an unclear mechanism [57]. Despite the numerous investigations of AR role in NSCCL, its role in SCLC is not understood or researched well enough.

A third limiting factor in studies is the collection time of blood and other biological specimens. Both factors are of crucial importance in studying T levels as the hormone exhibits diurnal variation with peaks and troughs throughout the day [59][60].

A final challenge that is posed in the performed studies includes the measurement method of T in LC. T is mostly found circulating in its bound form to albumin or the protein sex-binding hormone globulin (SBHG) and less than 2% is found in its free, bioactive form [14]. To improve hormone detection, blood-based association studies that measure free T can be performed and LC-MS/MS can be used as a precise quantification technique as opposed to immunoassays [61].

6. Conclusions

In line with the growing body of research on the role ARs play in LC, the interest in their therapeutic targeting is increasing. Further investigation at the genomic and SP level of A and AR in LC is required; this could be performed using probing methods or analyzing high-throughput datasets with the goal of identifying novel biomarkers and potential SP therapeutic targets. Additionally, investigations of post-translational modifications (PTMs) could offer insights into the biochemical regulation of the protein and pave the way for new avenues of research. With all novel findings, there is increasing hope that targeting the AR SP can provide relief for patients diagnosed with this deadly disease.

This entry is adapted from the peer-reviewed paper 10.3390/endocrines4020022

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