Co-expression of estrogen receptor beta and aromatase in Japanese lung cancer patients: Gender-dependent clinical outcome

Aim: The potential gender differences in lung cancer development have been proposed on the basis of hormonal actions. We aimed to evaluate whether estrogen receptors (ERs) in non-small cell carcinoma (NSCLC) patients may primarily depend upon intratumoral estrogen produced via aromatase pathway. Main methods: We evaluated ER beta (ERβ) and aromatase status in 169 Japanese NSCLC patients through immunohistochemistry analysis (IHC). Significance of IHC was further confirmed in NSCLC cell lines via in vitro assays. Key findings: IHC analysis of NSCLC patients demonstrated that both ERβ and aromatase were highly co-expressed (p = 0.032) in carcinoma cells. Overall survival in males was significantly worse than that in postmenopausal female among double positive NSCLC patients (p = 0.010) but not in non-double positive patients. In addition, among double positive cases, overall survival of males was significantly worse than that of postmenopausal females in those with higher ERβ Allred score ≥ 5, (p = 0.034), but not in those with lower ERβ Allred score = 3-4. In-vitro analysis demonstrated aromatase activity on testosterone treatment, which resulted in in situ estrogen production (p < 0.0001) and increased proliferation of ERβ overexpressing A549 cells (p < 0.0001). Aromatase inhibitor i.e. letrozole abrogated this proliferation and also enhanced the androgenic activity (p < 0.0001). Testosterone treatment resulted in estrogen responsive elements activation (p < 0.0001) in ERβ vector transfected A549 and LK87 cells whereas ER blocker i.e. fulvestrant abrogated this effect, (p < 0.0001). Significance: Our results suggest that co-expression of ERβ and aromatase in NSCLCs of Japanese males may result in tumor progression and potential endocrine therapy may confer therapeutic benefits to these patients.