Our comparison of all ER iso forms with

Our comparison of all ERα (iso)forms with ERβ immunostaining suggests that overall ERβ expression is lower than that of ERα isoforms. This contrasts the so far reported data for ERs in the lung, but is not a paradox; in pathology routine, ER positivity is defined stricto senso by nuclear WT ERs. As WT ERβ is mainly nuclear, it could easily be overestimated over extranuclear ERα variants. Our data raise the question on the criteria of ERα evaluation in the lung, as they exclude a priori the most prevalent ERs (extranuclear variants). As we show here, it is the localization of ERα immunoreactive molecules that makes the hallmark in variation within various cell types and gender, non-tumor versus tumor tissue and exhibits differential diagnosis potential for different NSCLC types. ERα identification can determine differential diagnosis of primary or metastatic nature of pulmonary tumor masses. The controversies on ERα protein detection in NSCLC [45], [63], [71], [72] could be (at least) partially attributed to the use of GSK2194069 receptor that have been optimized for use in tissues other than the lung (e.g. breast), or the non-incorporation of ERα nuclear or extra-nuclear localization. Even if there are several reports on the “gender gap” in NSCLC, it is not clear whether this should be attributed only to hormonal status, receptor profile and/or receptor functions and signaling [10], [11], [15]. The characteristics of our study population did not allow generation of significant conclusions on the role of menopausal status of the females we examined (as the majority of included females were postmenopausal). Nevertheless, the fact that a clear sex difference is still observed at post-menopausal age in normal lung is suggestive of an effect not only under the strict control of circulating estrogen, but also related to lung steroidogenesis per se, or other sex-related genetic and micro-environmental factors. This is supported by the meta-analysis of transcriptome probe-sets, in which a significant correlation of ERα variant transcription and sex, in normal lung, but not in NSCLC, is also revealed. Contrariwise, in NSCLC tumors and cell lines it is the histology subtype, rather than sex that defines the ER profile.
Conflict of interest
Introduction Cadmium (Cd), a heavy metal and one of the most toxic transition metals, has been classified as an important human carcinogen by the International Agency for Research on Cancer (IARC) and the United States National Toxicology Program (NTP) (Aquino et al., 2012; Brama et al., 2007; Nagata et al., 2013). Following the expansion of urbanization and industrialization, the amount of environmental Cd has increased (Nampoothiri and Gupta, 2006). Different investigations have shown that many countries and regions in the world are threatened to varying degrees of Cd contamination (Byrne et al., 2013; Chan et al., 2006). One of Cd chemical forms, Cadmium Chloride (CdCl2), is used extensively in chemical engineering, electroplating, and nuclear industries and it can easily release into the environment and contaminate water, air, foods, and plants. The presence of this toxic metal in cigarettes and environmental air pollution is well documented and suggests its role in the increased incidence of several human cancers. It accumulates and persists 15–20 years in the human soft tissues and leads irreversible damage to many organ systems including the female reproductive systems (Satarug et al., 2011). It can promote the proliferation of cancer cells and induce cancer by multiple mechanisms such as oxidative stress, aberrant gene expression, inhibition of DNA repair and apoptosis (Julin et al., 2011; Jin et al., 2003). Moreover, some studies have demonstrated that Cd as a metalloestrogen can bind to estrogen receptor (ER) and mimics the estrogen activity (Aquino et al., 2012; Johnson et al., 2003; Siewit et al., 2010). Exposure to environmental endocrine disruptors and the ability of these pollutants to bind ER were drawn the hypothesis of their role in the carcinogenesis, incidence, and etiology of hormone-related cancers such as breast, uterine, prostate and ovarian cancers (Brama et al., 2007; Byrne et al., 2013). Ovarian cancer as the most lethal gynecologic malignancy causes over 140,000 deaths annually worldwide (Sieh et al., 2013) and the survival rate of this disease is poor with 50% case fatality rate because of the diagnosis in the advanced stages (Jemal et al., 2008; Vargas, 2014). Epidemiological data have demonstrated that endogenous and exogenous estrogens can be effective in ovarian cancer pathogenesis (Lau et al., 1999).