ERa prevents tumorigenesis of both liver and breast cancer cells through CCN5

Estrogen receptor alpha (ERa)-mediated estrogen signaling has also shown to prevent hepatic tumori-genesis in mice. Consistent with this, hormone replacement therapy with estrogen supplementation dramatically reduced the risk of hepatocellular carcinoma. Silencing of ERa is also a key event for the transformation of ERa-positive breast cancer cells into malignant triple-negative breast cancer cells. However, the mechanisms underlying ERa-mediated prevention of both hepatic and mammary tumor-igenesis in humans are still unclear. Here, we present a functional genomics study of ERa targeting by comparing human liver cancer cells with human breast cancer cells using "loss or gain of function" genetic assays of ERa in vitro and in vivo. We discover that cellular communication network factor 5 (CCN5) is a direct downstream target of ERa; ERa suppresses growth and prevents tumorigenesis and malignant transformation of both liver and breast cancer cells through CCN5 in humans. The ERa-CCN5 regulatory axis functions as suppressors for both hepatic and mammary tumors, which is a common mechanism of preventing tumorigenesis for both liver cancer and breast cancer in humans. & COPY; 2023 Elsevier Inc. All rights reserved.