Joyce Slingerland, MD, PhD, FRCP(C)

2009-2010 BCRF Project:
(made possible with generous support from The Housewares Charity Foundation)

In the last few years, Dr. Slingerland's BCRF-funded work showed that combining conventional anti-estrogens (anastrozole and fulvestrant) with a new molecular targeted drug that blocks the oncogene Src can overcome resistance to hormonal therapy in ER positive breast cancer models. Combined use of a new Src inhibitor drug that is in development for cancer treatment together with either of two drugs in current use in the clinic (anastrozole, an aromatase inhibitor drug, or the estrogen receptor blocker fulvestrant) can more effectively reduce growth of human breast cancers in laboratory models than either drug alone. Based on these results, the Slingerland team has initiated a clinical trial using anastrozole and the Src inhibitor together in women with breast cancer. Work is underway to test anti-tumor effects of MEK and Src inhibition together with antiestrogens.

Breast and other human cancers appear to be driven by a small population of progenitor or stem cells. This year, the researchers showed that fulvestrant and AZD0530 together not only block tumor growth better than either drug alone, but this drug combination also reduces breast cancer progenitor cell (also known as stem cells) self-renewal while chemotherapy increases the proportion of these cells.

In studies of normal human breast progenitors over the last year, the Slingerland laboratory found that fat cells (which surround breast cells in the female body), stimulate breast epithelial cell growth when these two cell types are cultured together. They are currently characterizing the growth factors produced when normal human fat and epithelial cells are grown together and how these influence breast stem cells and mammary duct formation in 3-dimensional models. While stem cells are thought to be immortal, normal human mammary epithelial cells (HMEC) undergo senescence as these cell populations age with serial propagation in cell culture. The present grant will test how growth signaling, cell cycle, motility and the ability to form 3D branching duct structures from normal HMEC-derived stem/progenitor cells change as the HMEC approach the end of their finite lifespan. The stem cells in a cancer may be the real culprits and resist radiation and chemotherapy treatment. By better understanding how breast stem cell growth is regulated in normal and cancer-derived populations, the researchers hope to develop more powerful treatments and avoid resistance to therapy for breast cancer.

Mid-Year Progress Report:
Dr. Slingerland and colleagues have been investigating why obesity increases the risk of breast cancer by studying the effect of fat cells on the growth of breast epithelial cells (the cells that give rise to breast cancers). They have found that when grown together with fat cells (or adipocytes), breast epithelial cells grow faster and are more motile and show greater self-renewal compared to cells grown alone. When breast epithelial cells are grown with fat cells, this increases the production of growth factors by both cell types compared to when each cell type is grown alone. The researchers have identified six different growth factors (called cytokines) that are overproduced when breast epithelial and fat cells are grown together. Individually, some of these factors stimulate increased growth of breast cells, increase their motility (which could contribute to tumor metastasis or spread in the body) and stimulate the self-renewal of the stem cells in both normal breast epithelial cells and in malignantly transformed breast cells. They are currently investigating whether these cytokines can actually increase the ability of the cancer cells to invade into tissues and promote the establishment of metastatic cancers in laboratory models.

Additionally, the Slingerland lab has been testing how growth signaling, cell cycle, motility and stem cell properties change as normal human mammary epithelial cells approach the end of their finite lifespan. The stem cells in a cancer may be the real culprits and resist radiation and chemotherapy treatment. By better understanding how breast stem cell growth is regulated in normal and cancer-derived populations, the researchers hope to develop more powerful treatments and avoid resistance to therapy for breast cancer.

Bio:
A native of Canada, Dr. Slingerland received her MD from the University of Toronto in 1983, followed by a Fellowship in Internal Medicine with the Royal College of Physicians and Surgeons in Canada. In 1987, she was certified by the American Board in Internal Medicine and in Medical Oncology by the Royal College of Physicians and Surgeons. In August of 2002, Dr. Slingerland came to the University of Miami Miller School of Medicine as the Director of the Braman Breast Cancer Institute, Sylvester Comprehensive Cancer Center (SCCC) where she has worked to expand and coordinate research efforts on breast cancer from many disciplines. In addition, she is co-leader of the Breast Cancer Program at SCCC, and a tenured Professor in the Departments of Medicine and Biochemistry & Molecular Biology.

Dr. Slingerland discovered the cell cycle inhibitor p27 and her research investigates regulation of the G1 to S phase transition and how the cell cycle regulators are disrupted in cancer through aberrant signal transduction. Current work also investigates reversal of antiestrogen resistance in breast cancer through targeted therapies. She has published over 70 articles and reviews in addition to several book chapters and has received numerous awards. Dr. Slingerland continues her medical practice devoted entirely to breast cancer patients at the Sylvester Comprehensive Cancer Center and the Jackson Memorial Hospital.