Researchers investigate GPER receptor as possible new drug target for breast cancer

Five-year breast cancer survival rates have improved dramatically over the past 50 years, but tumors can recur up to ten or more years after they are detected. When tumors recur, they are even more difficult to treat. Recurring breast tumors often don't respond to targeted drugs, even if the initial tumor did, and they metastasize-spread to other parts of the body-more easily. To help women battling breast cancer, Eric Prossnitz, PhD, is investigating GPER, a new type of estrogen receptor, as a possible new drug target. Unlike "classical" estrogen receptors ER-a and ER-b, GPER resides on cell membranes rather than in the cell's nucleus. Dr. Prossnitz is a University of New Mexico Professor of Cell Biology & Physiology and Co-Leader of the Women's Cancers Program at the UNM Cancer Center. He recently received a 5-year, $1.6 million grant from the National Cancer Institute to study GPER, its role in resistance to drugs that target estrogen receptors, and possible new ways to target it in combating breast cancer.

Like other cell membrane receptors, GPER tells the cell what's happening around it. Much like humans see and hear their surroundings, each cell has different types of receptors to sense its environment. For example, breast cells have multiple receptors, including hormone receptors that sense estrogen and progesterone and a group of receptors that senses growth factors, which includes the HER2 receptor. Most breast cancer drugs target one or more of these receptors. Women whose breast cancer cells lack all three receptors, called triple negative breast cancers, must resort to surgery, chemotherapy and radiation. Dr. Prossnitz discovered in previous research that Tamoxifen, a breast cancer drug that works by inhibiting ER-a receptors, activates GPER. Now Dr. Prossnitz wants to determine whether and how GPER influences breast tumor growth and metastasis.

Dr. Prossnitz is collaborating with Helen Hathaway, PhD, UNM Professor of Cell Biology & Physiology and a member of the Women's Cancers Program, to conduct studies on GPER. In the first study, Drs. Prossnitz and Hathaway will use cancerous and non-cancerous breast cells to discover the differences in biochemical reactions that estrogen receptors and GPER trigger. Both receptors ultimately stimulate enzymes that regulate cell growth and survival, but researchers know little about how the cascades of cellular reactions differ. Understanding this biochemistry will help Drs. Prossnitz and Hathaway explain how breast cancer cells respond to estrogen and become resistant to Tamoxifen, potentially resulting in better long-term breast cancer therapies.

In the second set of studies, Drs. Prossnitz and Hathaway will use mice lacking the gene for GPER to determine whether GPER affects how breast cancers form and progress. They will also evaluate whether GPER affects the ability of the primary tumors to metastasize. Dr. Prossnitz explains, "The primary tumor rarely kills women. But when the tumor spreads to another site in the body and affects the function of an organ, that can kill." Drs. Prossnitz and Hathaway will also test different combinations of drugs to develop potential therapies that could inhibit both ER-a, the dominant estrogen receptor in breast cancers, and GPER receptors. Such a therapy could prevent acquired resistance to existing breast cancer drugs and targeting GPER alone could be a new strategy for triple negative breast cancers.

In their final set of studies, Drs. Prossnitz and Hathaway will use small pieces of live human breast tumors and normal breast tissue to test different therapies and GPER function. These small pieces of tissue include not only the breast cells, cancerous or not, but also the surrounding cells and matrix. "Cells behave very differently in tissues," explains Dr. Prossnitz. "They respond to what their neighbors are doing, and to the kinds of neighboring cells. To understand their behavior in people, we have to study the cells in the environment similar to what they had in the person." This set of studies will also test if the therapies that work for mouse breast tumors can also work in human breast cancers. "We need to understand how the whole tissue actually responds," says Dr. Prossnitz. "It's a crucial step towards clinical trials."

Before initiating clinical trials, researchers must demonstrate that the drugs are safe for humans in preclinical trials. But Drs. Prossnitz and Hathaway are encouraged. "Our compounds are not toxic to mice, even at very high doses," says Dr. Hathaway. Even so, clinical trials are years away because cancer is such a complex disease. "Nevertheless, this is an exciting new target for the treatment of millions of women with breast cancer," says Dr. Prossnitz. And for them, a new target means new hope.