Estrogen Receptor Isoforms Are Down-Regulated In Hepatocellular Carcinoma

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Estrogen receptor alpha (ERα) translocates to the nucleus and induces gene expression upon activation. The estrogen receptor is a target of US Food and Drug Administration FDA approved drugs such as the selective estrogen receptor degrader called Fulvestrant, which is indicated to treat breast cancer. ERα may also play a role in the development of hepatocellular carcinoma (HCC).

There are four known isoforms of ERα. The main estrogen receptor isoform is called as ERα66. The ER-α36 isoform does not interact with the genome, but activates MAPK/ERK, PI3K/Akt, and other signaling pathways. The relative importance of ERα66 and ERα36 in HCC was not known.

Wei Zou of Liaoning Normal University, Dalian, China and colleagues, investigated the expression pattern of estrogen and receptor isoforms in serum exosomes of HCC. Two hundred and thirty people were recruited at the Department of Biobank from January 2015 to January 2018 in the Affiliated Sixth People’s Hospital of Dalian Medical University. The results were published in the journal Clinical and Translational Medicine.

Using immunohistochemistry it was demonstrated that ER-α66 and ER-α36 are expressed in both HCC and normal liver tissue. Estrogen hormone was significantly lower in the blood in HCC patients compared to cirrhosis patients. ER-α66 and ER-α36 were also significantly downregulated in HCC.


Lower ER-α66 and ER-α36 mRNA levels was a predictor of HCC compared to normal adjacent liver tissue. The area under the ROC curve (AUC) of ER-α66 mRNA and that of ER-α36 mRNA was 0.876 and 0.842 respectively. ER-α36 mRNA was also downregulated in exosomes from HCC. ER-α66 mRNA was barely detectable in exosomes.

The study did not address why ER-α66 was expressed in HCC tumour samples, but not in HCC derived exosomes or indeed why ER-α was down-regulated in general. This may be important and was a limitation of the study.

“Exosomes are carriers of biologically active substances, and are ideal materials for liquid biopsy. However, there are few reports that described mRNA in exosomes for the diagnosis of human HCC. In this study, we discovered that ER- α36 was present in the exosome of the patients with HCC and ER-α36 mRNA was significantly downregulated in exosome from HCC patients. In addition, the ROC curve showed that ER-𝛼36 mRNA in exosomes could effectively distinguish the patients with chronic liver disease and HCC, suggesting that ER-α36 mRNA may serve as a good diagnostic biomarker for HCC. However, we barely detected ER-α66 mRNA in the exosomes. The exact reason for the low abundance of ER-α66 in the exosomes from HCC patients needs to be further investigated,” stated the authors.