Epidemiological data indicated that the incidence and mor- tality of hepatocellular carcinoma (HCC) in males are higher than that in females. 1 In 2018, the ratio of the number of cases to deaths in men and women was about 2.5:1 and 2.3:1, respectively. However, the incidence of HCC in post- menopausal women is significantly higher, which is almost equal to the incidence of men, 2 suggesting that the estrogen- signaling pathways play a vital role in development of HCC. The estrogen receptor alpha 66 (ER-), commonly used as a breast cancer marker, is a well-known mitogenic nuclear receptor. 3 It has been reported that ER-??66 is involved in the development of HCC. 4 However, the role of ER-??66 in the diagnosis of HCC is uncertain. The estrogen receptor alpha 36 (ER-6) is a novel estrogen receptor variant discovered by Wang et al in 2005. 5 Studies have shown that ER-??36 mediates the non-genomic effects of estrogen and participates in the progress of different cancers through MAPK/ERK, PI3K/Akt, and other signaling pathways. 6,7 Studies have also shown that the signal-regulating loop formed by ER- 36 and EGFR can affect the proliferation of HCC, 8 but its role in the diagnosis of HCC has not been reported before.
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