Sagar
Ghosh,
Ph.D.
Assistant Professor / Research
Profile and Contact Information |
Research
RESEARCH
Research Program
Objective
Breast cancer is one of the most threatening diseases not only in northern America but all over the world. Role of adipose tissue in breast cancer development is well documented, but the effect of microenvironment in fat tissue on cancer development is still not clear. Recent reports of obesity and breast density as high risk factors of breast cancer development strengthens the idea that stromal cells in fat tissue plays a major role in breast cancer development. Our research is primarily focused on how the microenvironment regulates the disease initiation and progression and the role of stroma in cancer biology. We employ biochemical, molecular biological and cell biological approaches along with animal model to study the adipose tissue biology and to address our questions.
Role of adipose stromal cell on steroid biosynthesis and breast cancer initiation
In the present study we have been utilizing adipose tissues isolated from patients of various medical backgrounds and histories, to explore mechanism behind adipose stromal cell-induced breast cancer development. This study will be beneficial to measure an individual’s risk on developing cancer and also for an early intervention of the disease. Using the primary cultures isolated from obese individuals we established the role of BRCA1, a tumor suppressor, on the regulation of aromatase, a key enzyme in estrogen biosynthesis. This study suggested a probable answer to the age-old conundrum on BRCA1’s role in tissue specific cancer development. Inflammation and various cytokines are greatly associated with obesity and biology of fat. In a very recent finding we also discovered a unique role of IKKβ on estrogen biosynthesis. Our present work focuses on various mouse models and xenograft studies to establish role of BRAC1 and IKKβ of stromal fraction in initiating cancer development. We believe that this study will lead us to find out few potential targets of breast cancer initiation factors which can be tested in pre-clinical studies.
Shape change and effect of altered cellular structure on cancer development
Changes in cell shape or rigidity of the microenvironment affect the patterns of gene expression and cell growth. Recent findings indicate that extracellular mechanical forces can alter a cell’s behavior by changing cellular architecture and plays a critical role in regulating cell phenotype. Our recent study has also indicated global changes in gene expression that takes place during the cellular architectural alteration of adipose stromal cells. Preliminary study revealed massive changes of several cancer-associated factors and extra-cellular matrix proteins during the cellular structural alteration that may play significant role in tumor biology as well as adipose biology. We are further characterizing the cause and effect of those cancer-related factors due to shape change in tumor context.
Identification of a stromal fraction with high cancer initiation potential
Stromal fraction isolated from adipose tissue is a heterogeneous population containing pre-adipocytes, fibroblasts, resident macrophages, multi-potent progenitor stem cells and other types of cells. Recent study on carcinoma associated fibroblasts (CAF) or mesenchymal stem cells (MSC) revealed their direct role in tumor progression, migration and invasion. One area of our research is focused on identifying a cellular fraction of adipose tissue that might play the significant role in steroid biosynthesis and thereby tumor development. We are using various CD markers and fluorescence-based reporter system to achieve our goal and our ultimate aim is to test this sub-population back in xenograft mouse model to test their efficacy in tumor development. This study may lead us to identify, target and eliminate a cancer-initiating sub-population of stromal fraction.
Selected Publications
- Ghosh S, Hu Y, and Li R: Cell Density is a Critical Determinant of Aromatase Expression in Adipose Stromal Cells. J Steroid Biochem and Mol Biol. In Press. (2009)
- Walter M, Sitai L, Ghosh S, Hornsby P, and Li R: Interleukin 6 Secreted from Adipose Stromal Cells Promotes Migration and Invasion of Breast Cancer Cells. Oncogene. 28(30): 2745-2755. (2009)
- Ghosh S, Choudary A, Ghosh S, Musi N, Hu Y, and Li R: IKKβ Mediates Cell Shape-Induced Aromatase Expression and Estrogen Biosynthesis in Adipose Stromal Cells. Mol Endocrinol. 23(5): 662-670. (2009)
- Ghosh S, Lu Y, and Hu Y: A Role of CREB in BRCA1 Constitutive Promoter Activity and Aromatase Basal Expression. Intl J Biomedical Sci. 4(4): 260-265. (2008)
- Sun J, Watkins G, Blair AL, Moskaluk C, Ghosh S, Jiang WG, and Li R: Deregulation of cofactor of BRCA1 expression in breast cancer cells. J Cell Biochem. 103(6): 1798-1807. (2008)
- Ghosh S, Lu Y, Katz A, Hu Y, and Li R: Tumor suppressor BRCA1 inhibits a breast cancer-associated promoter of the aromatase gene (CYP19) in human adipose stromal cells. Am J Physiol Endocrinol Metab. 292(1) E246-E252. (2007)
- Hu YF, Ghosh S, Amleh A, Yue W, Lu Y, Katz A, and Li R: Modulation of aromatase expression by BRCA1: a possible link to tissue-specific tumor suppression. Oncogene. 24(56): 8343-8348. (2005)
- Ghosh S, Wu Y, Li R, and Hu Y: Jun proteins modulate the ovary-specific promoter of aromatase gene in ovarian granulosa cells via a cAMP-responsive element. Oncogene. 24(13): 2236-2246. (2005)
- Wu Y, Ghosh S, Nishi Y, Yanase T, Nawata H, and Hu Y: The orphan nuclear receptors NURR1 and NGFI-B modulate aromatase gene expression in ovarian granulosa cells: a possible mechanism for repression of aromatase expression upon luteinizing hormone surge. Endocrinology. 146(1): 237-246. (2005)