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Traci Lyons lab | University of Colorado Cancer Center

Turning Off the Breast Cancer Switch: Federal Grant Powers Study of Therapy Resistance

It’s the latest project in a long, fruitful research partnership for CU Cancer Center members Traci Lyons, PhD, and Virginia Borges, MD.

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Written by Mark Harden on April 9, 2024

With support from a $3.3 million federal grant, a pair of University of Colorado Cancer Center members will investigate how a molecule they’ve been studying for a decade is able to promote resistance to therapies for a major type of breast cancer – and how to switch off the molecule’s harmful interference.

The molecule – known as semaphorin 7A, or SEMA7A – “promotes pretty much every hallmark of cancer. It increases cell growth, cell migration, cell invasion, the ability to survive in harsh conditions, such as what a cancer cell will encounter while traveling from one site in the body to the other, and ultimately it promotes metastasis,” the cancer’s spread, says Traci Lyons, PhD, an associate professor in the CU Division of Medical Oncology.

> VIDEO: Traci Lyons, PhD, discusses breast cancer research, specifically in women who have given birth.

“Most recently, we observed that it can promote resistance to anti-estrogen therapy and chemotherapy. So the overall goal of the project is to figure out how to reverse these mechanisms of therapeutic resistance, so that the tumor cells will now respond to the therapies.”

Lyons is the lead principal investigator on the five-year project, which starts this month, along with her longtime research collaborator and mentor, Virginia Borges, MD, a professor of medical oncology; and another frequent collaborator, Weston Porter, PhD, a professor at Texas A&M University. The $3.3 million R01 research project grant is from the National Institutes of Health.

Understanding the switch

The team will focus on understanding resistance to therapies in estrogen receptor positive (ER+) breast cancers, which represent about three-quarters of all breast cancer cases. The name means that the cancer cells have receptors – proteins on the cells – that can respond to estrogen hormones, which tell the cell to grow.

There are targeted therapies for ER+ breast cancers, yet more than two-thirds of breast cancer deaths are attributed to metastatic ER+ disease, partly because of the therapy resistance promoted by SEMA7A, Lyons says.

> CU Cancer Center Members Receive Grants to Conduct High-Tech Research

Lyons says she and Porter will investigate what she describes as a “molecular light switch” that turns the progression of breast cancer on and off. The switch involves another molecule called SIM2s, which is associated with tumor suppression in breast cancer. Porter is a leading expert on SIM2s biology and signaling in breast cancer.

“When SEMA is on, it promotes all the things that are advantageous for the tumor and bad for the patient,” she says. “And SIM2s turns it off by preventing SEMA from being made in the first place. So, we’re looking at how we can use the switch to turn SEMA off.”

Borges will perform analysis of the molecules involved in the SIM2s/SEMA7A switch in patients “and correlate that back to how the patient responded to their therapy,” Lyons says. “So, we’ll be able to look at these molecules in our patient samples and say, OK, what was their outcome?”

Lyons, meanwhile, will work in the lab to determine “whether restoring this switch via some readily available inhibitors could make patients more sensitive to their therapy and improve their outcomes. And if we can’t restore that SIM2s switch, can we turn off SEMA in some other way?”

A research partnership

Lyons and Borges have had a long and fruitful research partnership focused on breast cancer – a partnership that was highlighted by CU Anschutz Medical Campus Chancellor Don Elliman in his State of the Campus address last November. Elliman noted that the two have formed a startup biotech company, Pearl Scientific, to develop a novel monoclonal antibody therapy for breast cancer.

Lyons joined the CU School of Medicine in 1999 as a professional research assistant in the Department of Microbiology with David Barton, PhD; completed doctoral studies in molecular biology in the Department of Pathology with Steven Anderson, PhD; and moved on to a postdoctoral fellowship in the Young Women’s Breast Cancer Translational Program under the guidance of Borges and Pepper Schedin, PhD.

> Promising New Research for Metastatic Breast Cancer

Lyons’ and Borges’ research focus has been postpartum breast cancer – cancers diagnosed within 10 years of giving birth. Borges “noticed in her clinic that these women were having very bad outcomes,” Lyons says. “Many of our postpartum patients don’t respond to therapy. That research led us to find SEMA7A as a bad actor.”

Lyons says the CU Cancer Center and the CU Anschutz Medical Campus have provided “absolutely essential” resources for her team’s work, including the cancer center’s Flow Cytometry Shared Resource and Cell Technologies Shared Resource as well as the Biobank at the campus’ Colorado Center for Personalized Medicine.

Photo at top: Traci Lyons, PhD, a work in the lab. Photo by CU Cancer Center.

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Traci Lyons, PhD