Sesterterpene MHO7 suppresses breast cancer cells as a novel estrogen receptor degrader

Abstract Breast cancer, the most prevalent cancer in women, remains the second in the list of cancer mortality, the majority of these fatalities resulted from estrogen receptor alpha (ERα) positive disease. ERα is well known for its function on breast cancer initiation and development and has become the most successful biomarker in breast cancers. Ophiobolins are sesterterpene compounds with a distinct tricyclic 5-8-5 ring and have presented anti-cancer activities. MHO7(6-epi-ophiobolin G)was isolated from products of a mangrove fungus in our previous research and demonstrated robust activity against breast cancer cells (BCCs). The investigation on the precise mechanism of MHO7 shows that MHO7 acts as a novel ERα down regulator different from the known molecules in ER + breast cancer cells. A whole-genome transcriptomic analysis on MCF-7 cells treated with MHO7 revealed the estrogen signaling pathway was the most affected pathway, and further evidence showed the de novo synthesis of ESR1 mRNA was inhibited. In addition, MHO7 down-regulated ERα at the protein level through multiple approaches. It not only bound to ERα, pushing helix 11 away in the agonist conformation but also increased the ERα degradation through the ubiquitin-proteasome system. These effects consequently caused decreasing of the transcriptional activity of ER modulation which was confirmed by the decreasing of estrogen receptor element (ERE) activity as well as downstream genes expressions like GREB1, BRCA1, MUC1 and CCND1. Combination of tamoxifen and MHO7 yield a synergistic effect on the inhibition of MCF-7 cells when treated around the IC50 values. Our results suggest that MHO7 is a very promising drug candidate and provides a novel drug version on ERα down-regulation to fighting with breast cancer.