Sylvester Study Shows RAC1 Protein Plays Essential Role in Treatment-Resistant Breast Cancer

 In a study published in the journal Oncogene, researchers with Sylvester Comprehensive Cancer Center at the University of Miami’s Miller School of Medicine have shown that the RAC1 protein is an essential component in the estrogen receptor (ER) complex in ER+ breast cancers. These findings could lead to more effective therapies to treat therapy-resistant, ER+ tumors and possibly other cancers.

“We’ve shown the RAC1 protein is directly involved in estrogen receptor transcription activation as a cofactor within the ER complex,” said Jun Sun, Ph.D., a research assistant professor in the Nimer Lab and first author on the paper. “As a result, RAC1 signaling can modulate estrogen receptor activity.”

Around 80% of breast cancers are ER+, making estrogen a critical target to control the disease. Many patients are prescribed anti-estrogen therapies, such as tamoxifen, or other treatments that mitigate estrogen’s ability to drive tumors. However, over time, many cancers learn to live without estrogen, generating an urgent need for more advanced anti-cancer strategies.

Led by principal investigators Stephen Nimer, M.D., who directs the Cancer Center, and Professor Emeritus Marc Lippman, M.D., the research team pursued a different strategy to control estrogen. Rather than modulate the hormone itself, they focused on the receptor that receives and ultimately transmits the estrogen signals that make these breast tumors grow.

Inhibiting the Protein

Because RAC1 is a crucial component in the estrogen receptor complex, inhibiting the protein could have a major impact on the disease, particularly in patients whose cancers resist anti-estrogen treatments.

“Blocking RAC1 activity provides a unique mechanism to control estrogen receptor activity,” Sun said. “A clinical therapeutic agent that inhibits RAC1 could potentially treat ER+ breast cancers.”

The study illuminated how RAC1 is an essential player in ER function, helping it activate genes that modulate ER+ breast cancer progression. Reducing RAC1 levels significantly altered expression levels in 2251 genes. As a result, RAC1 inhibition reduced ER activity, as well as ER protein levels, short-circuiting estrogen signaling.

“This research is important not only because we have identified a potentially new target for breast cancer treatment, but also it reflects a collaboration of several labs within Sylvester that have taken a multidisciplinary approach to conducting novel cancer research,” Nimer said.

These benefits may not be limited to ER+ breast cancer. The research team believes RAC1 may also play a significant role in prostate and possibly other hormone-driven tumors.

“We have shown that RAC1 interacts with other nuclear receptors, such as the androgen receptor, which is important in prostate cancer,” Sun said. “As a result, RAC1 could be a therapeutic target for AR+ prostate cancer and other diseases. We are continuing to dissect these mechanisms to better understand the potential of RAC1 inhibition.”

Tags: breast cancer, Dr. Stephen Nimer, Dr. Sun Jun, Marc Lippman, Oncogene journal, Sylvester Comprehensive Cancer Center