Kathryn B. Horwitz, PhD
2012-2013 BCRF Project:
(made possible by generous support from Play for P.I.N.K.)
University of Colorado School of Medicine
“Madam, you have three breast cancers.” Can you imagine more shocking news? Unfortunately this scenario is common when it comes to estrogen receptor positive (ER+), also known as “luminal” cancers. It has been estimated that 70% to 75% of breast cancers are “luminal,” or positive for estrogen (ER) or progesterone (PR) receptors and dependent on estrogens for growth. However, half of luminal cancers contain an ER- negative and PR- negative “luminobasal” cell subpopulation akin to aggressive, triple negative basal-like disease. This means that if one were to analyze each cell in the luminal tumor individually, one would find numerous and different cell subtypes. The implications are sobering. For example, women with luminal breast cancers are routinely treated with hormone therapies. However, in most cases only one cell type among several in her tumor is ER+ and adequately targeted by such treatments. The other cells in her cancer would be hormone resistant from the start, and no alternative treatments are known. Dr. Horwitz’s research focuses on the characterization of the different cell types that are present in a single luminal tumor, so that each cell type can be specifically targeted with existing cancer therapies. Findings from this project will help enhance clinical tools and provide insights into how to potentially prevent therapy resistance that often occurs in cancer treatment.
Mid-year Progress: Dr. Horwitz's laboratory studies the most common breast cancers, called "luminal." Their cells contain receptors for women's hormones, making them "hormone-dependent." Therapies blocking access and supply of hormone have as a result been developed as treatment for this subtype of breast cancer. However, here is the problem: when scientists analyze luminal cancers on a cell-by-cell basis, they find that most tumors are actually mixtures of different cell types. Some cells are bona fide "luminal" with the expected receptors that would respond to hormone therapies. But other cells in the same cancer lack receptors and would be hormone-resistant. Indeed, a simple analysis of a single cancer reveals four cell subpopulations, each of which would theoretically require different treatment.
In this BCRF-funded project, Dr. Horwitz's team is isolating different luminal tumor cell subpopulations. They are learning how each cell forms, what stimulates it to grow, and how to target it for treatment. In the last few months, they have isolated and purified one of the receptor negative cell types (dubbed "luminobasal"). They then used a set of 89 FDA-approved cancer drugs, to show that EGFR-inhibitors suppress luminobasal cells. The sensible next experiment is to test the idea that in Luminal cancers with luminal/luminobasal-cell mixtures, combining hormone-therapy with EGFR-inhibitors is more effective than either treatment alone. If this works, then clinical trials of the combination therapy would follow.
Secondly, Dr. Horwitz's team thinks that another unusual cell (dubbed "double positive") is the progenitor for other cells in luminal disease. They recently succeeded in isolating these cells. "Double positive" cells will be used to test the theory that they are progenitors of other luminal-cell types. Dr. Horwitz plans to characterize "double positive" cells in detail and find drugs that kill or suppress them.
In sum, Dr. Horwitz's team believes that if the multiple cell populations in a mixed-cell luminal breast cancer can be individually targeted for treatment, women would likely survive the disease and live long and productive lives. Their goal is to find such treatments.
Dr. Horwitz is a graduate of Barnard College, received a Master's degree from New York University, and a Doctoral degree from the University of Texas, Southwestern Medical School in Dallas. She then joined the Department of Medicine faculty at the University of Colorado's School of Medicine, where she was rapidly promoted to Professor. She has received many awards and recognitions for her work. The University of Colorado has recognized her extensive service to the University, and to the local, national and international community of scientists and patients, by naming her a "Distinguished Professor" of the University, an accolade reserved for only a handful of professors on the four university campuses. In addition, Dr. Horwitz received the 2010 Fred Conrad Koch Award, The Endocrine Society's highest award.