Kathryn Horwitz, Ph.D.
University of Colorado
Denver, Colorado

Improving Breast Cancer Treatments

Hormones are vital substances produced by the endocrine system and carried through the bloodstream. They control the metabolism of cells, impact growth and regulate the body's response to stress or illness. Hormones also influence sexual development. Estrogen and progesterone are female sex hormones produced mostly by the ovaries that play a significant role in breast development and uterine function.

In women, estrogen and progesterone stimulate cell division and therefore stimulate growth in the breast and uterus. But because these cells divide more rapidly, they also have a higher likelihood of becoming malignant, which is characterized by quick, out-of-control growth. Therefore, prolonged exposure to sex hormones enhances a woman's likelihood of developing breast cancer. In fact, if her ovaries are removed before age 35, her likelihood of developing breast cancer is reduced by more than 95 percent.

So, a more thorough understanding of how sex hormones influence tumor growth can have a profound impact on established treatments for breast and uterine cancers in women.

Project Director Expertise

Kathryn Horwitz, PhD, is Professor of Endocrinology and Molecular Biology at the University of Colorado Health Sciences Center in Denver, Colorado. As a leading NFCR Project Director, she is committed to understanding the role that sex hormones play in the development and progression of breast cancer-and to finding better long-term treatments to fight this devastating disease, which is the most common cancer in women.

NFCR Research Overview

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Previous research by other scientists had confirmed that estrogen acts as a hormonal agonist, which means that it can stimulate tumor growth. In doing so, estrogen travels to different sites within the body that have estrogen receptors, such as the breast. Once there, it binds to these receptors inside the cell where it can activate breast cancer.

That is why Dr. Horwitz has explored how to block this hormonal agonist activity by using hormonal antagonists, like tamoxifen. A common drug treatment for breast cancer, tamoxifen blocks agonist or tumor-causing activity by binding to estrogen receptors in the cell and effectively turning off the agonist activity of the hormone.

Sometimes, however, hormonal antagonists such as tamoxifen stop working. Tumors may initially respond to tamoxifen by shrinking, but then may become resistant and resume growing. In fact, antagonists may actually become agonists, stimulating tumor growth rather than suppressing it. To solve this problem, Dr. Horwitz's work has focused on uncovering the factors that cause antagonists like tamoxifen to transform into cancer-causing agonists - and to finding a way to prevent that switch from happening.

So, a more thorough understanding of how sex hormones influence tumor growth can have a profound impact on established treatments for breast and uterine cancers in women.

NFCR Research Findings

Estrogen receptors long have been an important indicator of whether hormonal antagonists such as tamoxifen will be an effective treatment for some breast tumors. Through her research, however, Dr. Horwitz was the first scientist to discover that progesterone also plays an important role in breast cancer. Through intensive study, she identified progesterone receptors in breast tumors and showed that these markers were an even better predictor of whether a tumor would respond to tamoxifen treatment.

As a result of her finding, pathologists routinely conduct chemical tests to identify if both estrogen and progesterone receptors are present when a tumor is surgically removed. The presence of both receptors indicates that estrogen receptors are working properly and will therefore respond to tamoxifen treatment. In fact, 80 to 90 percent of breast tumors with progesterone receptors respond favorably to tamoxifen.

Dr. Horwitz has also conducted research to determine what factors may cause tamoxifen to stop working or to switch into a tumor-causing agonist. Specifically, she identified proteins that bind to hormone receptors and either stimulate or inhibit tamoxifen. A coactivator protein stimulates tumor growth, while a corepressor protein inhibits tumor growth. The ratio of these coactivator and corepressor proteins may determine a tumor's response to tamoxifen. Dr. Horwitz is currently studying whether her hypothesis is correct, using tumors from patients who initially responded to tamoxifen but then became resistant to the medication.

Future Research Goals

Dr. Horwitz's upcoming research will seek new ways to control the ratio of coactivators and corepressors in an effort to improve a tumor's response to tamoxifen. If she can increase the number of corepressors and decrease the number of coactivators, she may be able to stop the tumor from developing resistance to antagonists. This would increase the effectiveness of tamoxifen because the drug could be administered for longer periods without breast cancer patients building up a resistance to the medication.

Impact on Cancer Prevention, Treatment, or Cure

Dr. Horwitz has made significant contributions to the understanding and treatment of breast cancer. She has identified a very reliable way to predict which tumors will respond to tamoxifen treatment. She also is conducting important research to determine why tamoxifen changes from an antagonist to an agonist in some tumors, and is working to find ways to stop this change from taking place. Her work may lead to improved treatment strategies and the identification of more effective antagonists. With the continued support of the National Foundation for Cancer Research, Dr. Horwitz's work also will have a strong influence on the understanding and treatment of other hormone-related cancers, like uterine and prostate cancer.

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