Kathryn B. Horwitz, PhD

2007-2008 BCRF Project:
Made possible by generous support from Play For P.I.N.K.

More than 40,000 American women die of breast cancer each year because their primary tumors metastasize to sites beyond the breast. Seventy to 80% of all primary breast cancers contain receptors for women's hormones. These estrogen (ER) and/or progesterone (PR) receptors classify the tumors as "hormone dependent." Such tumors are treated with "hormone therapies" like tamoxifen or aromatase inhibitors. When tumor cells metastasize out of the breast, they do so by two routes - to the lymph nodes (LN) under the arms and from there into the blood and distant organs; or directly into the blood and distant organs.

Importantly, regardless of the route, metastatic tumors retain ER and PR. Tumors that spread to LNs are more than 80% likely to retain hormone receptors; tumors that spread directly via blood are ~67% likely to retain receptors. Therefore both types of advanced tumors are hormone dependent. At present, whether and how hormones influence breast cancer metastasis, is unknown. Also unknown is whether ER+ tumor cells growing in a metastatic environment (bone for instance) are as sensitive to hormone therapies as when those tumor cells are still in the breast.

It is the goal of Dr. Horwitz's project to develop and test new models of breast cancer metastasis that are ER-positive and hormone dependent so as to answer these questions. Current models of breast cancer metastasis almost uniformly use ER-negative human breast cancer cells. With BCRF support, she and her team are developing models of ER+ breast cancer metastasis that more accurately reflect the clinical situation. With BCRF funds, the researchers have developed a reliable model of ER+ human breast cancer LN metastasis. It shows that ER+ tumor cells in LNs are relatively estrogen resistant compared to the primary tumor. This means, the researchers think, that LN metastases of patients treated with hormone therapies would be poorly responsive.

They are using several approaches to develop reliable models of ER+ distant metastases. One, involving direct injection of cancer cells into the blood, indicates that hormones play a role in the number and size of bone metastases. Additional studies and approaches to generate metastases from ER+ solid tumors are underway. If successful, the studies would point to targeted methods that block the spread of breast cancers to lymph nodes, or their spread to more distant sites like the brain and bones. In the case of brain and bone, a hormone widely used by women for oral contraception and menopausal hormone replacement (namely progesterone) could turn out to protect against the spread of hormone dependent cancers to certain sites.

Mid-Year Progress Report:
Dr. Horwitz's research this fall has focused on the development of new models to study metastasis of ER+ breast cancers and the role of estrogens and progesterone on growth of cancers at distant sites. A surprising outcome of their study with progesterone is that it caused an increase in cells analogous to "cancer stem cells". Such cells are believed to be the originators of breast cancers. The researchers have followed up on this. They have identified an ER-negative (ER-) stem cell population in ER+ cancers. Importantly, while ER- themselves, these cells are capable of generating ER+ descendents that would produce ER+ cancers. This means, however, that hormone therapies which target the ER in ER+ cancers will not kill the stem cells, allowing the cancer to recur even if hormone treatment is ongoing. The recurrent cancer would be hormone resistant. If so, we need ways to target and kill the stem cells.

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.