Associate Professor and Interim Chair
Gerald & Flora Jo Mansfield Piltz Endowed Professor of Cancer Research
Ph.D. 1994, Department of Pharmacology and Cancer Therapeutics, Roswell Park Cancer Institute
Postdoctoral, Baylor College of Medicine
Estrogen receptor phosphorylation: A major focus of the laboratory is understanding the role of estrogen receptor alpha (ERα) phosphorylation in regulating receptor function and the mechanisms by which signaling pathway kinases/phosphatases alter function. These studies identify phosphorylation fingerprints for ERα that will impact tumor growth, migration/metastasis and response to endocrine therapy. These studies will provide the mechanistic groundwork for rational design of preclinical therapeutic combinations of endocrine therapy with agents that block or activate specific kinase signaling pathways.
Experimental therapeutics for estrogen receptor negative breast cancer: Although ER-negative breast cancer responds to conventional chemotherapy, patients relapse more frequently and have a worse prognosis compared to patients with ER-positive tumors. c-Src is an oncogenic non-receptor tyrosine kinase that is up-regulated in approximately half of all breast cancers. Unfortunately, single agent clinical Src inhibitors have produced very modest or no activity in clinical trials with breast cancer patients. KX-01 was developed as a ‘first in class’ peptidomimetic Src kinase inhibitor. Preclinical studies in the laboratory demonstrated that KX-01 treatment resulted in significant regression of ER-negative tumors and reduced metastasis to lung and liver in mouse xenografts. Remarkably, low dose KX-01 resulted in re-expression of ERα in ER-negative tumors and sensitization of these tumors to tamoxifen treatment.
Circadian regulation of estrogen receptor function: The impact of circadian disruption on nuclear receptor function is unknown. Artificial light at night is classified as a "probable human carcinogen" that contributes to circadian disruption. Extending this concept to estrogen receptor function during circadian disruption, female nude rats implanted with “tissue-isolated” MCF-7 breast cancer xenografts were housed in light boxes at 12/light:12/dark or exposed to dim light (0.2 lux) during the dark phase. Exposure to dim light resulted in markedly increased tumor growth and de novo resistance to tamoxifen that coincided with elevation of specific ERα phosphorylation sites. These collaborative studies with Steven Hill, Ph.D. and David Blask, M.D./Ph.D. demonstrated that increased ERα phosphorylation is a direct outcome of circadian disruption.
Adipocyte stem cells in reconstructive surgery and soft tissue repair: Adipocyte stem cells (ASCs) are present in adipose tissue and serve as precursors for mature adipocytes. Our research group is evaluating the use of ASCs in fat grafts for reconstructive surgery in breast and head/neck cancer patients. We found that the body mass index (BMI) of the patient donor profoundly impacts the viability, morphology and osteogenic differentiation of ASCs. Hypoxia that occurs in fat grafts markedly alters the ASC secretome and immunomodulation. Finally, ASCs stimulate metastasis of both breast cancer and head/neck tumors indicating caution when applying ASCs for reconstruction after tumor resection.
Metastatic breast tumor model developed from patient biopsies: Metastatic breast cancer is the leading cause of death in breast cancer patients. We developed a reproducible, hetero-transplant breast tumor model derived from primary needle biopsies from patients diagnosed with primary invasive ductal carcinoma. Tumors formed in mice exhibited a highly metastatic phenotype and enhanced tumorigenesis during metastatic latency in bone marrow.
Human adipose-derived Stromal/stem Cells induce functional CD4+CD25+FoxP3+CD127- regulatory T cells under low oxygen culture. Trivia P. Frazier, James McLachlan, Jeffrey M. Gimble, Hugh A. Tucker, and Brian G. Rowan. 2013 (under revision to Stem Cells and Development).
Disseminated breast cancer cells acquire a highly malignant and aggressive metastatic phenotype during metastatic latency in the bone. Carolyn G. Marsden, Mary Jo Wright, Latonya Carrier, Krzysztof Moroz, and Brian G. Rowan (2012). PLoS One. 2012;7(11):e47587. PMID:23173031
Peptidomimetic Src/pretubulin inhibitor KX-01 (KX2-391) as a single agent and in combination with paclitaxel suppresses growth and metastasis in human ER/PR/HER2-negative tumor xenografts in NUDE mice. Muralidharan Anbalagan, Alaa Ali, Ryan Jones, Carolyn Marsden, Mei Sheng, Latonya Carrier, Yahoa Bu, David Hangauer and Brian G. Rowan (2012). Mol Cancer Ther. 2012 Sep;11(9):1936-47. PMID: 22784709
Stable Inhibition of Specific Estrogen Receptor α (ERα) Phosphorylation Confers Increased Growth, Migration/Invasion, and Disruption of Estradiol Signaling in MCF-7 Breast Cancer Cells. Huderson BP, Duplessis TT, Williams CC, Seger HC, Marsden CG, Pouey KJ, Hill SM, Rowan BG. Endocrinology. 2012 153(9):4144-59. PMID: 22733972
Subcellular localization of total and activated Src kinase in African American and Caucasian breast cancer. Anbalagan M, Moroz K, Ali A, Carrier L, Glodowski S, Rowan BG. PLoS One. 2012;7(3):e33017. Epub 2012 Mar 22. PMID: 22457730
Post-translational modifications of nuclear receptors and human disease. Anbalagan M, Huderson B, Murphy L, Rowan BG. Nucl Recept Signal. 2012;10:e001. Epub 2012 Feb 27. Review. PMID: 22438791
Phosphorylation of Estrogen Receptor α at serine 118 directs recruitment of promoter complexes and gene-specific transcription. Duplessis TT, Williams CC, Hill SM, Rowan BG. Endocrinology. 2011 Jun;152(6):2517-26. Epub 2011 Apr 19. PMID: 21505052
Identification of four novel phosphorylation sites in estrogen receptor alpha: impact on receptor-dependent gene expression and phosphorylation by protein kinase CK2. Williams CC, Basu A, El-Gharbawy A, Carrier LM, Smith CL, Rowan BG. BMC Biochem. 2009 Dec 31;10:36. PMID: 20043841
The Src kinase pathway promotes tamoxifen agonist action in Ishikawa endometrial cells through phosphorylation-dependent stabilization of estrogen receptor (alpha) promoter interaction and elevated steroid receptor coactivator 1 activity. Shah YM, Rowan BG. Mol Endocrinol. 2005 Mar;19(3):732-48. Epub 2004 Nov 4. PMID: 15528270
SRC kinase and mitogen-activated protein kinases in the progression from normal to malignant endometrium. Desouki MM, Rowan BG. Clin Cancer Res. 2004 Jan 15;10(2):546-55. PMID: 14760076
Tulane University School of Medicine, Dept. of SCB, New Orleans, LA 70112 504-988-5255 email@example.com