Sylvester Comprehensive Cancer Center

Joyce M. Slingerland, M.D., Ph.D., F.R.C.P.(C)

Joyce M. Slingerland, M.D., Ph.D., F.R.C.P.(C)

Professor of Medicine; Director, Braman Family Breast Cancer Institute; Associate Director for Translational Research, Sylvester Comprehensive Cancer Center

Description of Research

Dr. Slingerland’s research investigates how cancers escape negative growth controls. Slingerland discovered a key of cell cycle inhibitor, p27, and went on to demonstrate that p27 levels are reduced in up to 60 percent of common human cancers (breast, prostate, lung, ovarian, and others) in association with poor patient prognosis. Her group showed that the therapeutic effect of anti-estrogens in ER positive breast cancer requires the Cdk inhibitors p21 and p27 to mediate growth arrest. Moreover, the group showed oncogenic activation of signaling via Src and mitogen-activated protein kinase (MAPK) pathways deregulates p27, providing a rationale for combined use of Src and MEK inhibitors with antiestrogens in therapy fo ER+ breast cancer. Her research group demonstrated that checkpoint loss during cancer progression makes p27 an essential mediator of arrest by both TGF-beta and by ER blockade. Dr. Slingerland’s studies have shown functional inactivation of p27 in human cancers can occur either through accelerated p27 degradation or through altered p27 phosphorylation leading to p27 mislocalization. Her team also showed that activation of signaling via the receptor tyrosine kinases and the phosphoinositol 3’ kinase pathway alters p27 phosphorylation and function and the protein accumulates in the cytoplasm away from its targets in the nucleus. Ongoing research is investigating how PI3K dependent p27 phosphorylation events contribute to cell motility, invasion and metastasis using in vivo tumor models. In addition to increasing RhoA binding and inhibition, p27 phosphorylations at T157 and T198 appear to affect other mediators of invasion. This work links oncogene activation with loss or inactivation of the cell cycle inhibitor, p27, elucidating a major mechanism of loss of growth control in cancer progression.

A second RO1 funded project investigates how estrogen binding to the ER stimulates recruitment of Src and ER binding to a number of ubiquitin ligases. These ligases may serve dual functions, as ER-coactivators and as ubiquitin ligases to promote estrogen stimulated, transcription coupled ER proteolysis. To date the lab has found that the E3 ligases, E6-associated protein (E6-AP) and BrCa1 both appear to act as dual co-activators and mediators of ER proteolysis. The potential gain of function of certain BrCa1 mutations that predispose to human breast cancer is under investigation. Ongoing work suggests that ER proteolysis may regulate both activation of ER-mediated gene expression coupled to ER proteolysis.

Highlights

  • Discovered that a key inhibitor of cell cycle progression, p27, is reduced in up to 60% of common human cancers (breast, prostate, lung, ovarian and others) and is associated with poor prognosis
  • Demonstrated that the therapeutic effect of antiestrogens in breast cancer requires the cdk inhibitors p21 and p27 to mediate growth arrest
  • Showed that activation of phosphoinositol 3’ kinase pathway alters p27 phosphorylation and sequesters the protein away from its targets in the nucleus - linking oncogene activation with loss/inactivation of p27
  • Oncogenic PI3K activation of multiple downstream kinases (AKT, SGK, RSK and mTOR) all increase cytoplasmic p27pT157pT198 which binds and inhibits RhoA to promote increased cell motility. Knockdown of p27 abrogates the excess metastasis of the MDA-MB-231-4175. This identifies cytoplasmic p27 as predictor of PI3K activation in human tumors.
  • Showed ligand activated ER recruits Src which phosphorylates the ER, increases E6AP binding and stimulates both ER and Src dependent activity at ER target genes coupled to ER proteolysis.

Selected Cancer-Related Publications

  • Chen Y, Guggisberg N, Jorda M, Gonzalez-Angulo A, Hennessy B, Mills GB, Tan CK, Slingerland JM. Combined Src and Aromatase Inhibition Impairs Human Breast Cancer Growth In vivo and Bypass Pathways Are Activated in AZD0530-Resistant Tumors. Clin Cancer Res 15:3396-405, 2009. Read more »
  • Larrea MD, Hong F, Wander SA, da Silva TG, Helfman D, Lannigan D, Smith JA, Slingerland JM. RSK1 drives p27Kip1 phosphorylation at T198 to promote RhoA inhibition and increase cell motility. Proc Natl Acad Sci U S A 106:9268-73, 2009. Read more »

Programs

Leader of the Multidisciplinary Research Program: Breast Cancer Program

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