James DiRenzo, PhD
Associate Professor of Medicine
University of California, San Diego School of Medicine, Ph.D. 1995
Norris Cotton Cancer Center
Pharmacology and Toxicology Graduate Program
Program in Experimental and Molecular Medicine
Dept. of Pharmacology and Toxicology
Dartmouth Medical School
Hanover NH 03755
Office: Remsen 611
Genetic control of self-renewal in a progenitor cell population during mammary gland differentiation. Application of the principles of tumor stem cell theory to translational breast cancer research.
Our laboratory is interested in the genetic control of cellular differentiation within the mammary gland. The epithelial portion of the mammary gland is a dynamic structure that undergoes successive regenerative cycles of proliferation, acquisition of physiologic function and cell death. The death of mature terminally differentiated cells is balanced by activities of basal progenitors, which must survive developmentally regulated cell death and re-initiate proliferation during re-population of the gland. During this proliferative phase, basal progenitors execute a critical decision to either retain their proliferative capacity and de-differentiated phenotype (self-renewal) or initiate a program of cellular differentiation (commitment). A critical determinant of this decision is the expression status of a member of the p53 family of transcriptional regulators called delta N-p63. Delta N-p63 directly opposes many of the activities of p53 by acting as a dominant negative regulator of p53-target genes. Several studies have shown that the expression of delta N-p63 is required for maintenance of self-renewal within the basal progenitor lineage. Other studies have shown that repression of delta N-p63 expression is required for commitment.
The major goals of our laboratory are:
1. To understand the mechanisms underlying the decision to self-renew or commit to differentiation by identifying factors which regulate transcriptional activity of the gene encoding delta N-p63. Recent studies from out lab demonstrate that delta N-p63 is a direct transcriptional of p53. This suggests that p53 may play a role in self-renewal by directing expression of a factor that opposes its downstream activities.
2. To understand the role of delta N-p63 in the preservation of basal progenitors during developmentally regulated apoptosis.
3. To identify downstream effectors of delta N-p63 that are expressed as a result of disruption of delta N-p63 expression or activity, and to determine the contributions of these genes to cellular differentiation.
The most reliable predictor of breast cancer risk is the length of a woman's reproductive life, which is proportional to the number of regenerative cycles within the mammary gland. Each regenerative cycle represents an opportunity for mutations to occur, and while the protective effects of apoptosis neutralize many of these mutations, others may be harbored and propagated within the subset of self-renewing progenitors that resist developmentally regulated apoptosis. In subsequent regenerative cycles, cells bearing such mutations may give rise to daughter cells that exit the progenitor compartment but fail to complete a program of terminal differentiation resulting in a growth or survival advantage. By doing so these cells may undergo additional mutations that further relieve constraints upon their growth and allow them to progress towards malignancy. This suggests that such cells would be ideal targets for chemo-prevention and underscores the importance of understanding the nature of the mammary progenitor cell and the genetic and endocrine signals that initiate cellular differentiation.
General Motors Cancer Research Foundation (DiRenzo) 01/07/02-01/06-04
Effects of p63 onp53 and Breast Cancer Growth.
The V Foundation for Cancer Research (DiRenzo) 11/1/2003-10/31/2005
Transcriptional Control of Multi-potency in Mammary Epithelia
Mary Kay Ash Charitable Foundation (DiRenzo) 7/1/2005-6/30/2007. Mammary Stem Cell Markers as Predictors of Breast Cancer Aggression.
Susan G. Komen Breast Cancer Foundation (DiRenzo) 4/1/2006-3/31/2008. Transgenic targeting of Mammary Stem Cells.
National Cancer Institute 1R01CA108539-01 (DiRenzo) (2005-2010) Role of delta N-p63 in Preservation of Self Renewal.
Medical Pharmacology, Molecular Pharmacology, Pathophysiology, Cancer Biology, PEMM 101, Experimental Protocols in Molecular Therapeutics
Dr. DiRenzo received his Ph.D. from the University of California, San Diego School of Medicine in 1995. He received post-doctoral training from 1995 through 1999 in the Department of Adult Oncology at the Dana Farber Cancer Institute at Harvard. Since 1999, he has continued his studies at the Dana Farber as an Instructor in Medicine. Dr. DiRenzo joined the Department of Pharmacology and Toxicology at Dartmouth as an Assistant Professor in the summer of 2001.
Li N, Singh S, Cherukuri P, Li H, Yuan Z, Ellisen LW, Wang B, Robbins D, Direnzo J. Reciprocal Intra-Epithelial Interactions between TP63 and Hedgehog Signaling Regulate Quiescence and Activation of Progenitor Elaboration by Mammary Stem Cells. Stem Cells. 2008 Feb 21. [Epub ahead of print] (view details on MedLine)
Li H, Cherukuri P, Li N, Cowling V, Spinella M, Cole M, Godwin AK, Wells W, DiRenzo J. Nestin is expressed in the basal/myoepithelial layer of the mammary gland and is a selective marker of basal epithelial breast tumors. Cancer Res. 2007 Jan 15;67(2):501-10. (view details on MedLine)
Li N, Li H, Cherukuri P, Farzan S, Harmes DC, DiRenzo J. TA-p63-gamma regulates expression of DeltaN-p63 in a manner that is sensitive to p53. Oncogene. 2006 Apr 13;25(16):2349-59. (view details on MedLine)
Harmes DC, Bresnick E, Lubin EA, Watson JK, Heim KE, Curtin JC, Suskind AM, Lamb J, DiRenzo J. Positive and negative regulation of deltaN-p63 promoter activity by p53 and deltaN-p63-alpha contributes to differential regulation of p53 target genes. Oncogene. 2003 Oct 23;22(48):7607-16. (view details on MedLine)
DiRenzo J, Signoretti S, Nakamura N, Rivera-Gonzalez R, Sellers W, Loda M, Brown M. Growth factor requirements and basal phenotype of an immortalized mammary epithelial cell line. Cancer Res. 2002 Jan 1;62(1):89-98. (view details on MedLine)