Biography
Dr. Slingerland received her M.D. from the University of Toronto in 1983. She is certified in Internal Medicine by the American Board in Internal Medicine and in Canada, and in Medical Oncology by the Royal College of Physicians and Surgeons. In 2002, Dr. Slingerland came to the University of Miami Miller School of Medicine as the Director of the Braman Family Breast Cancer Institute, Sylvester Comprehensive Cancer Center where she is working to expand and coordinate multidisciplinary breast cancer research. She has published over 60 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.
Dr. Slingerland's lab research has provided insights into how cancers escape negative growth controls. Following her discovery of a key cell cycle inhibitor, p27, she found that p27 levels are reduced in up to 60% of common human cancers (breast, prostate, lung, ovarian and others) in association with poor patient prognosis. She also showed that cell cycle inhibitors p15 and p27 cooperate to cause G1 arrest by transforming growth factor-beta (TGF-beta) and that cancer cells lose responsiveness to TGF-beta through loss or deregulation of p27. Current work addresses how p27 function is impaired in human breast and other cancers. Functional inactivation of p27 in human cancers can either occur through accelerated p27 degradation or through altered p27 phosphorylation leading to p27 mislocalization. Slingerland's group demonstrated that antiestrogen drugs require the cdk inhibitors p21 and p27 to arrest breast cancer growth. She showed that oncogenic signaling via the Src and MEK pathways deregulate p27 function causing tamoxifen resistance in breast cancer. Efforts to prevent or reverse hormone independent, antiestrogen resistant breast cancer growth using EGFR, MEK and Src inhibitors are under investigation in pre-clinical studies and clinical trials.
Abstract
Molecular Therapies for Hormone Resistant Breast Cancer
About two-thirds of breast cancers express the estrogen receptor (ER). These ER positive breast cancers can be treated with antiestrogen drugs like tamoxifen or aromatase inhibitors. Unfortunately, most breast cancers develop resistance to these drugs. Our lab has shown that estrogen promotes breast cancer growth by causing the degradation of a key cell cycle inhibitor, p27. We also showed that estrogen deprivation and drugs that block the ER, like tamoxifen, depend on p27 to cause breast cancer cells to stop growing. p27 levels are often reduced in human breast cancers and this predicts poor patient outcome and poor response to tamoxifen therapy. Our recent work showed that the oncogene Src acts on p27 to change its shape and function and promotes p27 degradation in breast cancer cells. This grant will investigate further how Src alters both where p27 is in the cell and how its function is regulated. We will examine a series of tissues from human breast cancer samples to test whether Src activation is associated with reduced p27 protein and if both of these findings together may predict poor patient outcome. Given the strength of our observations in the laboratory, we plan to test if a new Src inhibitor drug can delay or prevent resistance to antiestrogens therapy. We will carry out a Phase I-II clinical trial of the Src inhibitor, AZD0530, together with antiestrogens therapy for metastatic and locally advanced breast cancer. These studies will increase our understanding of the relationship between Src activation and loss of the growth inhibitory effect of p27 in human breast cancer, and apply this knowledge to design new more effective strategies to treat women with antiestrogens resistant breast cancer.