Brian G. Rowan, Ph.D.
Associate Professor
browan@tulane.edu

RESEARCH INTERESTS

Molecular Mechanisms of Nuclear Receptors in Hormone-Dependent Cancer: My research seeks to define the molecular mechanisms governing nuclear receptor action in breast/ovarian cancer with the aim of developing new therapies, and improving existing therapies for these malignancies. Current studies employ molecular techniques to examine the role of kinase signaling pathways, nuclear receptors/coregulators, the micronutrient selenium and bone marrow mesenchymal stem cells (MSCs) in regulating sensitivity and resistance to hormonal therapy in breast cancer. Findings from our studies directly support translational research to develop novel combination therapies for breast and other hormone-dependent cancers.

Nuclear Receptor and Coregulator Phosphorylation in Breast and Endometrial Cancer: A major focus of our research program is understanding the role of estrogen receptor and coregulator phosphorylation in regulating endocrine therapy for breast cancer and the mechanisms by which signaling pathway kinases/phosphatases alter estrogen receptor function. These studies will identify phosphorylation fingerprints for estrogen receptor and coregulators that are associated with gene-specific transcription. (J. Biol. Chem., 2000, Mol.Cell.Biol., 2000, Molecular Endocrinology, 2005, Molecular Endocrinology 2007). The current emphasis is on novel phosphorylation sites in estrogen receptors α and β. Related to these studies, we have also have examined active kinase expression (Clinical Cancer Research, 2004) and coregulator expression (Gynecologic Oncology,. 2004) during progression from normal to malignant human endometrium. The long-term goals of these collective studies are to provide the mechanistic groundwork for rational design of preclinical therapeutic combinations of endocrine therapy (selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs)) with agents that block or activate specific kinase signaling pathways.

Selenium Regulation of Nuclear Receptors in Cancer: A second major research focus is combination of the micronutrient selenium with endocrine therapy for breast cancer. In collaboration with investigators Roswell Park Cancer Institute, we have found that selenium inhibits estrogen receptor function in breast cancer cells and can reverse tamoxifen resistance, in part through downregulation of estrogen receptor (Breast Cancer Res. Treatment, 2005, Molecular Cancer Therapeutics, 2005). Current studies will identify the molecular mechanisms underlying the therapeutic efficacy of selenium combined with endocrine therapy for breast cancer.

The Role of Mesenchymal Stem Cells in Breast Cancer Metastasis to the Bone: A new research focus is discerning the role of adult, bone marrow mesenchymal stem cells (MSCs) in breast cancer metastasis to bone. Breast cancer metastasis to bone is a leading cause of breast cancer mortality and also results in a variety of painful complications that significantly impact patient quality of life.  Current knowledge of breast cancer metastases to bone is incomplete and therapies based on this knowledge are limited to palliative, but not preventive nor curative treatments. Mesenchymal stem cells (MSCs) are a critical component of the bone marrow microenvironment and new evidence is emerging that links MSCs to processes of breast cancer metastasis.  In collaboration with Drs. Steven Hill and Radhika Pochampally at Tulane University School of Medicine and the Center for Gene Therapy at Tulane, our proposed projects will test the hypothesis that human bone marrow MSCs regulated early breast cancer metastasis to bone by promoting adhesion/invasion and survival of breast cancer cells.

 

REPRESENTATIVE PUBLICATIONS

Al-Dhaheri, M. and Rowan, B.G. (2007) PKA exhibits selective modulation of estradiol dependent transcription in breast cancer cells that is associated with decreased ligand binding, altered ERα promoter interaction and changes in receptor phosphorylation. Molecular Endocrinology, 21(2):439-56.

Al-Dhaheri, M.H., Shah, Y.M., Basrur, V., Pind, S.N., and Rowan, B.G. (2006). Identification of novel 4-hydroxytamoxifen induced proteins in T47D breast cancer cells. Steroids, 71(11-12):966-978.

Koterba, K. and Rowan, B.G. (2006) Measuring ligand-dependent and ligand–independent interactions between  nuclear receptors and associated proteins using Bioluminescence Resonance Energy Transfer (BRET2). Nuclear Receptor Signaling, 4:e021

Al-Dhaheri, M. H. and Rowan, B. G. (2006) Application of phosphorylation site-specific antibodies to measure nuclear receptor signaling: characterization of novel phosphoantibodies for estrogen receptor α. Nuclear Receptor Signaling, 4:e007.

Shah, Y., Al-Dhaheri, M., Dong, Y., Ip, C., Rowan, B.G (2005). Selenium Disrupts Estrogen Receptor α Signaling and Restores Tamoxifen Sensitivity in Tamoxifen Resistant Breast and Endometrial Cancer Cells. Molecular Cancer Therapeutics, 4(8):1239.

Shah, Y., Kaul, A., Dong, Y., Ip, C., Rowan, B.G. (2005). Selenium inhibits estrogen receptor signaling in breast cancer through decreased expression of estrogen receptor α mRNA.  Breast Cancer Research and Treatment, 92(3):239-50.

Basu, A. and Rowan, B.G. (2005). Genes related to estrogen action in reproduction and breast cancer. Frontiers in Bioscience, 10:2346-72.

Shah, Y and Rowan, B.G. (2005). The Src Kinase Pathway Promotes Tamoxifen Agonist Action through Phosphorylation-Dependent Stabilization of Estrogen Receptor α Promoter Interaction and Elevated SRC-1 Activity. Molecular Endocrinology, 19(3):732-48.

Shah, Y., Basrur, V., Rowan, B.G. (2004).Selective Estrogen Receptor Modulator Regulated Proteins in Endometrial Cancer Cells. Molecular and Cellular Endocrinology, 219(1-2):127-139.

Desouki, M.M. and Rowan. B.G. (2004). Src Kinase and MAP Kinases in the Progression from Normal to Malignant Endometrium. Clinical Cancer Research, 10(2):546-55.

Kershah, S.M., Desouki, M.M., Koterba, K.L., Rowan. B.G. (2004) Expression of Estrogen Receptor Coregulators in Normal and Malignant Human Endometrium. Gynecologic Oncology, 92(1):304-13.

Rowan, B.G., Garrison, N., Weigel, N.L., and O'Malley, B.W. (2000) 8-Bromo cAMP induces phosphorylation of two sites in SRC-1 that facilitate ligand independent activation of the chicken progesterone receptor and are critical for functional cooperation between SRC-1 and CBP. Mol.Cell.Biol. 20(23): 8720.  

Rowan, B.G., Weigel, N.W., and O'Malley, B.W. (2000) Phosphorylation of Steroid Receptor Coactivator One: Identification of the Phosphorylation Sites and Phosphorylation through the Mitogen Activated Protein Kinase Pathway.  J. Biol. Chem. 275: 4475.