Our laboratory's research in signal transduction, cancer biology and therapeutics has two major goals. The first goal is to gain some understanding of the molecular mechanisms that have gone awry in cancer leading to the cancer's unregulated growth. With normal cells, growth-factors bind to growth-factor receptors and generate an intra-cellular signaling cascade of molecular reactions that results in cell proliferation. These signal-transduction pathways are aberrantly activated in many cancers, including carcinoma of the prostate and breast. Breast cancers frequently express one or more kinds of activated growth-factor receptors, and their presence correlates with poor patient prognosis. We reasoned that the level of activation of a downstream signaling protein in common to all of the receptors might provide an excellent indicator of patient prognosis (thereby helping to determine how aggressively to treat the patient). Additionally, if the activated growth-factor receptors were actually driving the unrelenting growth of the cancer cells, then this common signaling protein might itself serve as a therapeutic target. We have made several exciting findings:

1. the p52 Shc signaling protein (which helps to link growth-factor receptor signaling to the Ras and Myc pathways) is constitutively activated (tyrosine-phosphorylated) in most breast cancer cells;
2. the breast cancer cells (but not normal breast epithelial cells) require functional Shc protein in order to proliferate; similarly, prostatic carcinoma cells (PC-3 cells) require functional Shc for autocrine/paracrine IGF-1-receptor-driven transactivation of the EGF receptor, and consequentially, for growth in serum-free media and for growth as tumor xenografts in immunodeficient mice;
3. the expression levels of an inhibitory Shc isoform (p66), show a strong, inverse correlation with the level of activated p52 Shc, suggesting that it may be a new tumor suppressor associated with breast cancer. Indeed, forced re-expression of p66 Shc inhibits the tumorgenicity of breast tumors;
4. by immunohistochemical analysis, the relative level of tyrosine-phosphorylated Shc compared to p66-Shc in patients tumors has an unprecedented ability to identify aggressive malignancies that will recur after surgical removal of a patient's primary tumor.

The study of Shc in breast and prostatic cancer, then, should:

1. help to better predict patients with poor prognosis, thereby guiding therapeutic aggressiveness;
2. identify new therapeutic targets (Shc and its pathways) for treating breast and prostate cancers;
3. provide fundamental new insights into the molecular lesions that drive breast and prostatic cancers.

Stevenson, L. E., Frackelton, A. R. Jr. (1998) Constitutively tyrosine phosphorylated p52 Shc in breast cancer cells: correlation with ErbB2 and p66 Shc expression. Breast Cancer Res Treat. 49(2):119-28.

Stevenson, L. E., Ravichandran K. S., Frackelton A. R. Jr. (1999) Shc dominant negative disrupts cell cycle progression in both G0-G1 and G2-M of ErbB2-positive breast cancer cells. Cell Growth Differ. 10(1):61-71.

Boney, C.M., Gruppuso, P.A., Faris, R.A. and Frackelton, A. R., Jr. The critical role of Shc in IGF-I-mediated mitogenesis and differentiation in 3T3-L1 preadipocytes. Molecular Endocrinology 14: 805-813, 2000.

Filardo, E.J., Quinn, J.A., Bland, K.I. and Frackelton, A. R., Jr. Estrogen-induced activation of Erk-1 and Erk-2 requires the G-protein-coupled receptor homologue, GPR30, and occurs via transactivation of the EGF receptor through release of HB-EGF. Molecular Endocrinology 14(10): 1649-1660, 2000.

Boney, C.M., Sekimoto, H., Gruppuso, P.A. and Frackelton, A.R., Jr. Src family tyrosine kinases participate in insulin-like growth factor-I mitogenic signaling in 3T3-L1 cells.† Cell Growth and Differentiation 12(7):379-386, 2001.

Filardo, E.J., Quinn, J.A., Frackelton, A. R., Jr. and Bland, K.I. Estrogen action via the G-protein-coupled receptor, GPR30: stimulation of adenylyl cyclase and cAMP-mediated attenuation of the EGFR-to-MAP K signaling axis. Molecular Endocrinology 16(1): 70-84, 2002.

Associate Professor

Ph.D., Brown University, 1979

Roger Williams Hospital
Prior Hall, 2nd Floor

(401) 456-2320
A_Frackelton_Jr@brown.edu