New compound found to inhibit ER positive breast cancer
Approximately eighty percent of all breast cancers are estrogen receptor positive (ER+), meaning that the cancer relays on the hormone estrogen to grow. People with ER+ breast cancer are often treated with drugs that reduce the production of estrogen or block the estrogen receptor in cancer cells. But resistance to treatment eventually develops in a significant fraction of patients, and one important mechanism of drug resistance is genetic mutation. ER mutations are common in patients with metastatic breast cancer.
If we can find a way to overcome drug resistance, it would improve the outcomes of breast cancer patients. Scientists from the University of Texas Southwestern Medical Center have now designed a small molecule that suppresses the growth of breast cancer cells that are resistant to conventional therapies. The molecule, called ERX-11, exhibits anticancer activity in vitro and in vivo. The study, published in eLife, highlights the potential of molecules similar to ERX-11 in treating breast cancer.
The unique mechanism of ERX-11 action overcomes the limitations of current therapies, according to the first author Prof. Ganesh Raj.
ER signaling involves co-regulator proteins. Normally, the levels of ER co-regulators are tightly regulated by the body. A growing body of evidence shows that some ER co-regulators are elevated in breast cancer, including SRC3 (AIB1), SRC2, and PELP1. This deregulation correlates with mammary tumorigenesis, drug resistance and metastasis.
Prof. Raj and colleagues sought to find molecules that prevent ER from interacting with its co-regulator proteins. One compound, ERX-11, mimics a peptide that is important for the interactions between ER and its co-regulators. The researchers demonstrated that ERX-11 directly binds to ER and blocks the interaction of certain co-regulators with both native and mutant versions of ER.
The team also tested ERX-11 in breast tumor-bearing mice. Oral administration of ERX-11 to the mice led to much smaller tumors. Importantly, no obvious adverse effects were observed.
Using ER+ breast tumor samples derived from patients, the team revealed that ERX-11 treatment significantly reduced tumor cell proliferation. Moreover, ERX-11 decreased the ER levels. Finally, ERX-11 did not impact the proliferation of triple negative breast cancer.
In summary, the data suggest that the compound ERX-11 is able to inhibit ER co-regulator interactions and ER+ breast cancer growth. It is reasonable to test ERX-11 in further studies of breast cancer.
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