Kathryn B. Horwitz, PhD

2009-2010 BCRF Project:
(made possible by generous support from Play For P.I.N.K.)

In the past year Dr. Horwitz has published 10 papers citing BCRF support. She and her group continue research on two interrelated areas - hormone regulation of metastasis and role of stem cells. Women die of breast cancer because the primary tumors in their breasts recur locally or as distant metastases. Metastasis occurs when cancerous cells spill into blood, which then carries them far and wide and deposits them in distant organs. Importantly, if primary tumors within the breast are "luminal" (70% of all breast cancers) because they contain "receptors" for women's hormones, then subsequent metastases tend to be luminal as well. We know that these hormones, estrogens and progestins, control growth of luminal cancers within the breast. But, what is the role of women's hormones in breast cancer metastasis?

With BCRF support the researchers continue to develop and study models of luminal cancer metastasis that reflect the clinical situation. Initial data show that estrogens are needed for cancer cells to seed and grow at distant sites. On the other hand, the effects of progesterone vary - this hormone appears to block metastasis at some sites but promote metastasis at other sites. 2. The notion that breast cancers arise from stem cells remains controversial although acceptance of this idea is growing. Stem cells are rare cells within a cancer that slowly renew themselves, while at the same time generating progeny that divide rapidly, acquire new properties, and fuel the tumor's growth. It is thought that rare stem cells always lurk within the larger tumor mass, however. They are immortal, survive drug and hormone treatments, and drive disease recurrence and metastasis.

The Horwitz team published this year that luminal breast cancer stem cells are expanded by progesterone. They think this explains why women taking progestins for menopausal hormone replacement therapies (HRT) are at increased risk of breast cancer, and argue that these women have pre-existing, possibly dormant and undiagnosed micro-disease and do not know it. When they take progestins for HRT, the hormone awakens their tumor cells.

In 2009-2010 the researchers propose to use experimental and clinical samples to: 1. Study estrogens and progestins in metastasis of luminal breast cancers. 2. Further define stem cells in luminal disease; contrast stem cell survival in recurrent tumors after hormone and chemotherapies; and contrast stem cells and hormone receptors in rapidly recurring vs. dormant cancers (10 years or more).

Mid-Year Progress Report:
With BCRF support, Dr. Horwitz and colleagues are developing models using human breast cancer cells and clinical samples to ask: What role do women's hormones play in the spread of cancer to distant organs? Their initial studies indicate that estrogens fuel tumor seeding and growth at distant sites. Progesterone suppresses or exacerbates this growth, depending on the organ.

Dr. Horwtitz has recruited a postdoctoral fellow who is developing models to study the role of hormones in metastasis (Aim 1). Analysis of any breast cancer shows that it is composed of multiple cell types. That explains why breast cancer is so hard to cure: one cell type may respond to treatments while another is resistant. The researchers are studying a cell type in hormone dependent cancers that they call "luminobasal". These cells survive chemotherapies and hormone therapies (Aim 2). Luminobasal cells can be expanded or suppressed by estrogens and progestins and they are studying the mechanisms by which women’s hormones do this. If the numbers of luminobasal cells in a tumor can be reduced, it would make therapies more effective.

Bio:
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.