Sarah (Sally) J. Parsons
- BA, Valparaiso University, Valparaiso, IN
- PhD, Duke University, Durham, NC
- Postdoc, University of Virginia
- Professor, Microbiology, Immunology, and Cancer Biology
- Phone: 434-924-2352
- Email: firstname.lastname@example.org
Molecular mechanisms of Src family tyrosine kinases in mitogenesis, tumorigenesis, and neuronal activity.
Three major projects are currently underway in our lab. Two of them relate to breast cancer and one to prostate cancer. All of the studies have emanated from our original interest in the function of c-Src, a non-receptor tyrosine kinase, in normal and neoplastic cell physiology.
Project 1: Regulation of p190RhoGAP by c-Src P190RhoGAP is a multi-domain 190 kDa protein that localizes to the cytoplasm of cultured cells and appears to function as an inhibitor of cell proliferation and inducer of apoptosis. It contains a RhoGAP domain that activates the intrinsic GTPase activity of the Rho family of small GTPases, which regulate actin cytoskeleton rearrangements in response to growth factor or integrin stimulation. P190 is also tyrosine phosphorylated and a substrate of c-Src. We are investigating the role of p190RhoGAP in regulating growth factor- induced cytoskeleton rearrangements, cell cycle progression (cytokinesis), and apoptosis and how tyrosine phosphorylation by c-Src affects these roles in both normal fibroblasts and human breast cancer cells. Studies suggest that p190 functions as a tumor suppressor.
Project 2: Biological synergy between c-Src and the EGF receptor c-Src and the EGF receptor are co-overexpressed in a variety of human tumors, including breast cancer, suggesting that the the two tyrosine kinases may functionally interact and contribute to the progression of the disease. In murine fibroblasts and in human breast cancer cells, we have shown that c-Src potentiates the tumorigenic capability of the EGF receptor by phosphorylating an amino acid residue in the kinase domain of the receptor, Tyr 845, that appears to be required for both the mitogenic and tumorigenic function of the receptor. The requirement for this phosphorylation, in G-protein-coupled signaling pathways, in hormone signaling, and in cytokine signaling has also been demonstrated. The downstream signaling effectors of phosphorylated Tyr 845 are also being identified. They include STAT5b, a transcription factor, COX II (cytochrome c oxidase II of mitochondria), and others. Future studies focus on COX II, its regulation by the EGFR/c-Src, and how this regulation affects the bioenergetics of cancer cells vs. normal cells. In other studies we have shown that c-Src is required for growth of breast tumor cell lines. The intact SH2 domain and a catalytic-independent region of the kinase domain of c-Src are required for this effect. Efforts are underway to target the Tyr 845 of the EGF receptor and the SH2 and catalytic domains of c-Src for anti-cancer therapeutics and to understand its role in therapeutic resistance, with an emphasis on adriamycin–resistance in estrogen receptor positive breast cancer cells.
Based on our previous studies in chromaffin cells, we became intrigued with the presence and potential role of neuroendocrine (NE) cells in cancers of the prostate. NE cells are normal constituents of prostatic epithelium, but their numbers increase when the epithelium becomes neoplastic and progresses into metastasis. Several laboratories have observed that mitotic activity of cells surrounding NE cells is heightened, as compared to other regions of the gland, suggesting that NE cells secrete paracrine growth factors. Existing evidence also suggests that in tumors, NE cells derive from the tumor cells themselves by a putative mechanism of “trans” differentiation. We are investigating the mechanism by which NE cells become differentiated in LNCaP prostate tumor cells, whether differentiated NE cells secrete paracrine factors that influence growth, survival or migration of surrounding tumor cells, and whether the secreted factors utilize EGFR as a central conduit for their signaling events. The latter studies open the possibility of applying novel therapeutic approaches to the treatment of late stage prostate cancer, where few effective therapies are currently available.
- Ishizawar R, Miyake T, Parsons S. c-Src modulates ErbB2 and ErbB3 heterocomplex formation and function. Oncogene. 2006;26(24): 3503-10. PMID: 17173075
- Amorino G, Deeble P, Parsons S. Neurotensin stimulates mitogenesis of prostate cancer cells through a novel c-Src/Stat5b pathway. Oncogene. 2006;26(5): 745-56. PMID: 16862179
- Riggins R, Thomas K, Ta H, Wen J, Davis R, Schuh N, Donelan S, Owen K, Gibson M, Shupnik M, Silva C, Parsons S, Clarke R, Bouton A. Physical and functional interactions between Cas and c-Src induce tamoxifen resistance of breast cancer cells through pathways involving epidermal growth factor receptor and signal transducer and activator of transcription 5b. Cancer research. 2006;66(14): 7007-15. PMID: 16849545
- Marozkina N, Stiefel S, Frierson H, Parsons S. MMTV-EGF receptor transgene promotes preneoplastic conversion of multiple steroid hormone-responsive tissues. Journal of cellular biochemistry. 2007;103(6): 2010-8. PMID: 17960555
- Deeble P, Cox M, Frierson H, Sikes R, Palmer J, Davidson R, Casarez E, Amorino G, Parsons S. Androgen-independent growth and tumorigenesis of prostate cancer cells are enhanced by the presence of PKA-differentiated neuroendocrine cells. Cancer research. 2007;67(8): 3663-72. PMID: 17440078
- Demory M, Boerner J, Davidson R, Faust W, Miyake T, Lee I, Hüttemann M, Douglas R, Haddad G, Parsons S. Epidermal growth factor receptor translocation to the mitochondria: regulation and effect. The Journal of biological chemistry. 2009;284(52): 36592-604. PMID: 19840943 | PMCID: PMC2794774
- DaSilva J, Gioeli D, Weber M, Parsons S. The neuroendocrine-derived peptide parathyroid hormone-related protein promotes prostate cancer cell growth by stabilizing the androgen receptor. Cancer research. 2009;69(18): 7402-11. PMID: 19706771 | PMCID: PMC2803023
- Su L, Pertz O, Mikawa M, Hahn K, Parsons S. p190RhoGAP negatively regulates Rho activity at the cleavage furrow of mitotic cells. Experimental cell research. 2009;315(8): 1347-59. PMID: 19254711 | PMCID: PMC2731427
- Modesitt S, Parsons S. In vitro and in vivo histone deacetylase inhibitor therapy with vorinostat and paclitaxel in ovarian cancer models: does timing matter? Gynecologic oncology. 2010;119(2): 351-7. PMID: 20673975
- Manchinelly S, Miller J, Su L, Miyake T, Palmer L, Mikawa M, Parsons S. Mitotic down-regulation of p190RhoGAP is required for the successful completion of cytokinesis. The Journal of biological chemistry. 2010;285(35): 26923-32. PMID: 20534586 | PMCID: PMC2930692
- Slack-Davis J, Dasilva J, Parsons S. LKB1 and Src: antagonistic regulators of tumor growth and metastasis. Cancer cell. 2010;17(6): 527-9. PMID: 20541695
- Valerie N, Casarez E, Dasilva J, Dunlap-Brown M, Parsons S, Amorino G, Dziegielewski J. Inhibition of neurotensin receptor 1 selectively sensitizes prostate cancer to ionizing radiation. Cancer research. 2011;71(21): 6817-26. PMID: 21903767
- Miyake T, Parsons S. Functional interactions between Choline kinase α, epidermal growth factor receptor and c-Src in breast cancer cell proliferation. Oncogene. 2011;31(11): 1431-41. PMID: 21822308 | PMCID: PMC3213328
- Ludwig K, Parsons S. The Tumor Suppressor, p190RhoGAP, Differentially Initiates Apoptosis and Confers Docetaxel Sensitivity to Breast Cancer Cells. Genes & cancer. 2011;2(1): 20-30. PMID: 21779478 | PMCID: PMC3111004
- Pritchard J, Dillon P, Conaway M, Silva C, Parsons S. A Mechanistic Study of the Effect of Doxorubicin/Adriamycin on the Estrogen Response in a Breast Cancer Model. Oncology. 2012;83(6): 305-320. PMID: 22964943