The striking 3-4:1 male predominance of
esophageal squamous cell carcinoma (ESCC) has not yet been well explained. Our hypothesis is that the changes in level of
estrogen and/or subtype of
estrogen receptor (ER) may exert a protective factor in esophageal
carcinogenesis and prognosis of ESCC. Radioimmunoassay (RIA) was used to determine the serum level of
estradiol in healthy cohort from high-incidence area (HIA) and low-incidence area (LIA) for
esophageal cancer as well as patients with ESCC from HIA in Henan, northern China. The ERβ expression profiling during the multi-stage progression of ESCC pathogenesis was evaluated by immunohistochemistry (IHC). Both males and females from HIA had significant decreases of serum
estradiol in high-risk subjects predisposing for ESCC compared to healthy counterparts from LIA (P < 0.01). Furthermore, patients with ESCC from HIA developed the lowest level of
estradiol (P < 0.01). ERβ expressed in precursor lesions of ESCC and changed quantitatively and qualitatively with
disease progression during the multi-stages process of esophageal
carcinogenesis. High frequency of ERβ expression was correlated with less aggressive potential of clinical behavior (P = 0.012, 0.015 for
lymph node metastasis and
tumor stage, respectively). This study indicates that lower serum level of
estradiol may represent higher predisposition for development of ESCC, and ERβ expression and/or nuclear location may predict better outcome for patients with ESCC. The present results provide clues to explain the striking gender difference for ESCC, which warrants further investigations on potential applications of
estrogen or analogs in prevention of ESCC.