Oestrogen actions contribute to female gender-specific risks in the development of lung carcinoma

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Highlights

  • Recent findings point to a role of sex steroid hormones in lung cancer development and progression.

  • Steroid hormones may contribute to differences in the lung cancer risk for men and women with equivalent exposure to other risk factors.

  • Contradictions in the literature are likely to be due to the interaction between signalling initiated by different receptor isoforms.

Abstract

Lung cancer is increasing in incidence particularly among women, associated with a global change in smoking habits. Steroid hormones, particularly oestrogen exert an influence on tumour progression in tissues where their target receptor is expressed. Oestrogen receptor, particularly ERβ is highly expressed in the lung and becomes more highly expressed in lung carcinogenesis. Genes involved in the process of lung carcinoma progression and signalling cascades linked to invasion and angiogenesis are modulated by oestrogen receptors. This review intends to collate recently published evidence identifying a role for oestrogen in the initiation and progression of lung carcinoma and how these two processes are differentially affected by circulating oestrogens both in women and in men. Circulating oestrogens may be a significant risk factor in women’s susceptibility to lung carcinoma and also provide an additional approach for more targeted therapy.

Introduction

Lung cancer is the most commonly diagnosed cancer, with approximately 1.8 million new diagnoses in 2012 worldwide and 1.6 million associated deaths [1]. Tobacco smoking has long been established as the most important contributing factor in lung cancer development [[2], [3], [4]]. This is reflected in the greater prevalence of lung cancer in men than in women. In the US, there were 17 % more lung cancer deaths in men (78,694) than in women (67,155) in 2017, but this pattern is projected to reverse by 2045 as smoking trends have changed, and more young women are taking up smoking [5]. In the US over the 15 years from 1998 to 2012 the incidence of lung cancer declined from 60 cases per 100,000–45 cases per 100,000 in men, but the incidence for women remained stable at 30–35 cases per 100,000 [6]. This is also seen in epidemiology from many other countries where there is an increase in lung cancer diagnoses among women but a concurrent decline in men, the countries with the greatest increase in female lung cancer diagnoses are Brazil, Cyprus and Spain [1]. Although cigarette smoking is the most important single risk factor for lung cancer development in women, approximately 10%–15% of cases occur among never smokers, suggesting that other independent factors that play an important role in its aetiology [7]. Studies have shown a higher incidence rate for lung cancer than expected in women which is not fully explained by their smoking behaviours [[8], [9], [10]]. A study carried out in Norway found that women have an increased susceptibility to lung cancer compared to men with the same lifetime smoking exposure, and these observations suggest that female-specific factors also influence lung cancer development [9].

Men and women differ in terms of their lung cancer risk, postdiagnosis survival, tumour histology and even in the genetic mutations associated with malignancy [11]. In addition to smoking, the variation in lung cancer manifestation and its rate of occurrence among females and males has been variously hypothesized to be related to hormonal factors, genetic susceptibility and physiological influences [8]. For example, there is a lower proportion of small cell carcinoma (SCC) and a higher proportion of adenocarcinoma in women as compared to men [11]. In non-small cell lung cancer (NSCLC) patients, EGFR (Epidermal growth factor receptor) mutations are more frequent in female patients than in males (more than 40 % vs. less than 15 %). Among current smokers, female patients have a 3.9-fold greater median frequency of CYP1A1 (Cytochrome P450 1A1) mutation compared to males [11]. A comparison of the age specific incidence of lung cancer between men and women revealed that the incidence was almost equivalent up to the age of 50 years, after which the incidence increased much more rapidly in men than in women [12]. These observations raise questions about the role that female sex hormones, especially oestrogen, may have a role in the initiation and progression of lung tumours, possibly akin to its complex effects in breast and endometrial carcinoma.

In addition to its role in sexual differentiation, reproduction and homeostasis, oestrogen also contributes to the suppression and development of certain pathologies, particularly malignancy in various tissues, and it has postulated as one of the contributors to lung cancer development and subsequent progression [13]. The physiological effects of oestrogen are mediated through binding to structurally and functionally distinct oestrogen receptors, alpha and beta (ERα and ERβ) [14]. The two ERs display very different tissue distributions, with ERα highest in breast, ovarian, and endometrial tissues while ERβ is most abundant in the ovaries and the lung [15]. The importance of the oestrogen signaling pathway in various physiological, pathological functions and in carcinogenesis has been extensively investigated [13]. Accumulating evidence indicates that oestrogen levels are much higher in patients with lung cancer [16]. QuanFu Huang et al. have found that oestrogen stimulates interleukin-6 (IL6) expression to promote lung adenocarcinoma progression through the ERβ pathway [17]. Recent studies have found that oestrogen significantly upregulated IGF-1R expression, also via ERβ-mediated transcription and promoted murine lung adenocarcinoma progression [15,18].

There is evidence that menopause is associated with an increase in lung cancer risk [7], however the situation is more complex. A Chinese study found that postmenopausal women; those who experienced a later menopause; those with more lifetime ovulatory cycles and those with fewer pregnancies all experienced an increased risk for lung cancer development [11]. These are all factors that also contribute to a greater risk in the development of breast carcinoma through a greater life time exposure to 17β-estradiol. Another study found that female patients with NSCLC have a reduced risk of death and had a better benefit from treatment with EGFR inhibitors compared with men, suggesting that they may some protective benefit from circulating oestrogens, or through past exposure to oestrogens in this case [19]. Several studies have reported that exposure to hormone replacement therapy (HRT) is associated with adverse effects on lung cancer survival [16,20]. However, a meta-analysis study done in China found that HRT use was associated with a decreased risk of lung cancer development in women [21].

This review aims to investigate the sometimes contradictory, studies on the contribution of oestrogen and ER-mediated signalling to lung carcinoma development. We also summarize the impacts of xenoestrogens and endocrine disrupters of the lung on the prognosis and the risk for developing lung cancer. Additionally, for postmenopausal women, HRT is a further factor that may also impact on lung carcinoma risk.

Section snippets

Influence of oestrogen on NSCLC outcome

Oestrogen is a pleiotropic steroid hormone which plays a role in many physiological processes, not only in development of the female reproductive system and the maintenance of other secondary sex characteristics but also as a regulator of metabolism and other physiological processes throughout the body [22]. Many studies have demonstrated how oestrogen acts on different epithelia in the body to impact on whole body physiology [23]. Oestrogen is involved in lung development and function in both

Conclusion

Oestrogen has been implicated in lung development in both women and men since both genders express ER, and this expression increases in malignancy. ER expression is associated with lung carcinoma outcome in women, but interestingly, also in men. There is interplay between the ER and EGFR pathways suggested that ER blockade may help control or delay recurrence in EGFR + ve lung carcinoma. ERβ expression is significantly associated with poor prognosis in NSCLC patients, whereas ERα expression is

CRediT authorship contribution statement

Chi Sun Liau: Investigation, Writing - original draft. Praveena Mogan: Investigation, Writing - original draft. Warren Thomas: Conceptualization, Supervision, Writing - review & editing.

Declaration of Competing Interest

The authors report no declarations of interest.

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