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BCRF Researchers Identify Protein Associated with Metastasis and Drug Resistance

Discovery opens up potential new therapeutic options for ER-positive breast cancer patients.

A BCRF-supported study has connected a protein involved in embryonic development with drug resistance, offering a novel new avenue for targeted treatment.

The study, published in the journal Proceedings of the National Academy of Sciences (PNAS), links high activity of Forkhead Box Protein A1 (FOXA1) with resistance to anti-estrogen therapies and breast cancer metastasis. Spurred by findings from Dr. Xiaoyong Fu, a scientist and assistant professor in the laboratory of Dr. Rachel Schiff and Dr. Kent Osborne at Baylor College of Medicine (Houston), BCRF researchers from Memorial Sloan Kettering Cancer Center (New York) and Dana Farber Cancer Institute at Harvard Medical School (Boston) joined forces to identify a potential target for advanced breast cancer. A possible drug is in clinical trials for advanced cancer that may benefit a subset of breast cancer patients as well.

“This work reveals a novel new target in a well-known pathway of drug resistance,” Dr. Schiff said. “It represents just one example of how BCRF has enabled discovery research to lead us in new directions.”

Understanding resistance to anti-estrogen therapies

Drug resistance is a prominent hallmark of advanced breast cancers with poor prognosis. Even when effective therapies exist, as for the most common type of breast cancer—called estrogen receptor (ER)-positive, drug resistance can develop, sometimes many years after initial therapy.

Dr. Schiff’s research has focused on understanding how drug resistance occurs. “If we understand how resistance happens, we can develop models to study how to circumvent it,” she said.

One of the most well-known drivers of resistance to anti-estrogen (endocrine) therapies involve the estrogen receptor gene (ESR1). Mutations in ESR1 occur in about 30 percent of advanced ER-positive breast cancers, but less is known about other resistance mechanisms.

FOXA1 belongs to a group of proteins that regulate genes involved in early embryonic development. By co-opting factors like FOX, tumor cells can activate aggressive growth programs that allow them to survive anti-cancer treatments and activate metastatic processes.

Narrowing the focus

When Dr. Schiff’s team determined that FOXA1 promoted resistance to anti-estrogen drugs in breast cancer cells, they set out to identify potential targets that could counter this effect. “Because of its many functions, targeting FOXA1 itself would be toxic to healthy cells as well as cancer cells,” she said. This led the researchers to look at genes regulated by FOXA1, before ultimately identifying the protein hypoxia-inducible factor-2α (HIF-2α) as a key player in the development of resistance to anti-estrogen therapies.

“HIF-2α represents a new paradigm in endocrine resistance,” Dr. Schiff said. “Our paper shows that it activates a complex pro-metastatic program in ER-positive breast cancer cells with high FOXA1 and that it works independently of mutations in the ESR1 gene.”

Next steps

Discovering HIF-2α as a unique potential target of endocrine resistance opens up potential new therapeutic options to prevent or treat endocrine-resistant and metastatic disease. In fact, a drug that specifically targets HIF-2α is currently in clinical trials for advanced kidney cancer and a type of brain cancer called glioblastoma.

Dr. Schiff’s team will now test their findings in laboratory models of endocrine resistance and metastases.

“Our goal is to identify the FOXA1 program that is driving this effect, so that we can develop an effective strategy,” she said. “It’s never about targeting just one protein. Tumor cells will find a way around one target. We have to be able to shut down the program.”

Dr. Schiff is optimistic the HIF-2α inhibitor that is currently in clinical trials for other cancers will be effective for some breast cancers, but it will be important to identify biomarkers to determine what patients will be most likely to benefit. Part to this work is being done through her collaborations with BCRF investigators and others at Dana Farber (Myles Brown, Rinath Jeselsohn, and Nikhil Wagle) and Memorial Sloan Kettering Cancer Center (Jorge Reis-Filho) who are helping validate her laboratory findings in clinical samples.

What does this mean for patients?

While ER-positive breast cancer is very treatable and has a very good five-year survival rate with early diagnosis, this type of breast cancer can return many years later. These late recurrences suggest that there are already micro metastases—tumor cells that have escaped the primary tumor—at the time of diagnosis, even very early diagnosis.

The researchers hope that targeting a FOXA1 program through HIF-2α and other factors may be a strategy to prevent micro-metastases from becoming life-threatening cancers or offer a new option to halt the growth of metastases.

Dr. Schiff credits her BCRF funding not only for this discovery but all the work in her lab.

“BCRF is an enabler,” she said. “There is almost not one paper or one grant that our group has produced in the last 15 years that did not come from BCRF-supported work.”

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