‘Evil’ Proteins Are a Force for Good in Estrogen Receptor-Positive Breast Cancer

TUCSON, Ariz. – Breast cancer is one of the most common cancers in the United States, striking 1

out of 8 women. About 80 percent of all breast cancers are estrogen receptor-positive, in which cancer growth is fueled by estrogen.

Marco Padilla-Rodriguez, PhD, a recent graduate of the University of Arizona College of Medicine – Tucson’s Graduate Program in Molecular Medicine, untangled some of the mysteries of a protein called EVL — pronounced “evil” — which is thought to reduce the ability of ER-positive breast cancer to spread to other parts of the body.

As a graduate student, Dr. Padilla-Rodriguez collaborated with UA Cancer Center member Ghassan Mouneimne, PhD, assistant professor of cellular & molecular medicine, and a team of UA and international researchers who used epidemiological data to compare breast cancer patients taking hormone replacement therapy at the time of diagnosis with those who were not. They analyzed genetic data to identify EVL as an important regulator of cancer cells’ ability to spread, and conducted follow-up experiments in breast cancer cells.

The study results recently were published online in the open-access journal Nature Communications. Study contributors included investigators from the UA, Dana-Farber Cancer Institute, Howard Hughes Medical Institute and Institut de Recherche sur les Maladies Virales et Hépatiques in France.

Go or grow

ER-positive breast tumors are studded with estrogen receptors, which are like gas tanks that can be filled with estrogen, fueling cancer’s growth. Patients now are treated with surgery and chemotherapy, typically followed with anti-estrogenic drugs, such as tamoxifen, which reduce cancer recurrence by cutting off breast cancer cells’ fuel supply.

The estrogen story isn’t as “black and white” as many people believe, however. The “go or grow” model explains a key difference in cancer progression. Cancer is most dangerous when cells break free from the original tumor and travel to other areas of the body, a process called metastasis (“go”). But tumor cells can replicate (“grow”) without metastasizing, remaining contained in their original site. Although estrogen does increase risk for the initiation of breast cancer and fuel its growth, it does not seem to promote metastasis.

“In breast cancer, estrogen is connected to the growth of the tumor, but it also seems to suppress the ability of cancer to spread,” Dr. Padilla-Rodriguez said. “The growth of the tumor and the tumor’s ability to spread are not always linked. You might have a large tumor, but it stays contained. You might have a small tumor that spreads throughout the body.”

The Mouneimne Lab analyzed genetic datasets to identify EVL as a factor in taming estrogen’s cancerous effects, finding that estrogen enhances the production of EVL, which seems to keep cancer cells contained to the original tumor site. As estrogen levels fall, so do levels of EVL, freeing cancer cells to invade neighboring tissues — the first step in metastasis. EVL’s role in regulating a cell’s actin cytoskeleton could be the key to its ability to suppress cell movement.

“Cells have skeletons, just like we have a skeleton,” Dr. Padilla-Rodriguez explained. “Actin is one type of skeleton. Unlike our skeleton, actin can be remodeled, like Lego pieces being shaped into different structures.”

Depending on how a cell rearranges its actin cytoskeleton, it might be more likely to stay in one place, adhering to adjacent cells, or it could have the ability to migrate, crawling away from other cells like a microscopic caterpillar.

“Generally, cells like to cluster together,” Dr. Padilla-Rodriguez said. “When we treat them with anti-estrogenic drugs, actin allows the cell to break away and pull itself forward.”

One of the next steps is to learn how to leverage EVL’s interaction with estrogen to develop combination treatments for patients with ER-positive tumors. While anti-estrogenic drugs such as tamoxifen rein in tumor growth, they also might indirectly reduce EVL levels, accelerating remaining cancer cells’ invasion of neighboring tissues.

“With tamoxifen, you’re inhibiting the brakes,” Dr. Mouneimne said. “Now we want to go after the gas pedal to halt the cancer from progressing. Then we will be inhibiting both growth and invasion.”

In the future, perhaps a combination treatment could include standard anti-estrogenic drugs to inhibit tumor growth and incorporate a new drug capable of mimicking EVL’s ability to suppress a cancer cell’s mobility. This type of dual therapy could deliver a “one-two punch” to a tumor’s capacity both to “grow” and “go,” helping reduce tumor size while also keeping it contained in one location.

“Many researchers focus on shrinking the tumor, but we’re paying more attention to metastasis,” said Dr. Mouneimne. “The best treatment would target both.”

Dr. Mouneimne is working with Tech Launch Arizona to commercialize a method to measure EVL levels in ER-positive breast tumors, with the hope that someday such a diagnostic could be used to expand personalized medicine options for breast cancer patients.

Beyond good and evil

Drs. Padilla-Rodriguez and Mouneimne are wary of fostering distrust of anti-estrogenic drugs such as tamoxifen, which have been so successful in controlling the recurrence of breast cancer.

“Listen to your doctors,” Dr. Mouneimne said. “We’re not medical doctors and we haven’t done clinical studies. We certainly are not advocating for patients not to undergo anti-estrogenic therapy. We’re trying to understand the biology.”

Their quest to understand ER-positive breast cancer’s underlying biology is continuing to illuminate the role estrogen plays in cancer progression. The team has created time-lapse videos of breast cancer cells treated with estrogen, which stay in tight clusters, and breast cancer cells treated with tamoxifen, which spread out and break away. However, they do not want to sway public perception away from tamoxifen and other anti-estrogenic drugs.

“Estrogen is not good in some aspects of cancer, but might be good in other aspects,” Dr. Padilla-Rodriguez said. “I always thought anything that promotes cancer is always bad. Changing the script about estrogen would be a positive thing. It should not be viewed as either good or bad.”

For Dr. Padilla-Rodriguez, questions surrounding anti-estrogenic drugs are personal.

“My mom was diagnosed with ER-positive breast cancer in 2001,” he recalled. “She died in 2011. Those were 10 years, from when I was 9 years old to 19. Even though it ended much earlier than I ever wanted it to, that was very valuable time to have.”

He credits tamoxifen with keeping his mother alive during his formative years.

“The value of therapy is real,” Dr. Padilla-Rodriguez said. “I wouldn’t change how my mom received therapy.”

Despite his family’s connection to ER-positive breast cancer, Dr. Padilla-Rodriguez said it was happenstance that brought him to the Mouneimne Lab.

“I did not come in with the mission to solve my mother’s disease,” he said. “In science, you’re on a river. The river takes you places you weren’t intending to go, but you go there, and maybe you succeed. I felt like I made a contribution.”

This research was supported by National Cancer Institute (NCI) grant R01 CA196885-01, NCI diversity supplemental grant R01 CA196885-01, NCI University of Arizona Cancer Center Support Grant P30CA023074 and a Science Foundation Arizona Bisgrove Scholars Postdoctoral Fellowship.

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