Tan A. Ince, MD, PhD

2007-2008 BCRF Project:
The influence of both nature (genes) and nurture (environment) are important in determining the overall outcome of most complex biological processes. In breast cancers, the accumulation of mutations in genes has been intensively studied as a central mechanism defining malignant behavior and outcome. In this project the researchers study how the intracellular microenvironment of different cells influences the actions of mutated genes and the outcome of breast tumors.

Last year, Dr. Ince and his colleagues developed a chemically defined cell culture medium that allowed them to directly compare genetically identical tumors that were experimentally created from various distinct normal cell types in the human breast. This experiment revealed that tumor cell behavior is strongly influenced by the nature of the normal cell type that serves as the precursor of the tumor cells. Hence, the researchers predict that a comprehensive analysis of various normal cell types in the human breast will be important and instructive for understanding the nature of the tumors that arise from these cells.

Mid-Year Progress Report:
It has been known for several decades that cancer is caused by genetic mutations, which are changes in the DNA molecule itself. More recently scientists have discovered that epigenetic changes can also make important contributions to the development of cancer. Epigenetic literally means "on genes", and refers to wrapping of the linear DNA molecule around histone proteins. When the DNA molecule is wrapped around proteins it becomes 50,000 times more compact. The genes that are in the tightly packed DNA tend to be dormant and genes that are loosely packed tend to be active.

Dr. Ince's team developed a tumor model that provides evidence that these epigenetic changes play an important role in determining breast tumor behavior. The normal human breast tissue has many different cell types; among these, the researchers converted two different normal human breast cell types into tumorigenic cells through the introduction of an identical set of gene mutations. The resulting tumors differed significantly despite having identical DNA mutations. The tumors created from one cell type formed tumors in models when only 10 cells were injected, and these tumors frequently spread to the lungs; in contrast, the tumors derived from another normal breast cell never spread to other organs and required injection of 1,000,000 cells to form tumors in models.

Since the scientists used the same genetic mutations to induce these tumors, they conclude that the epigenetic differences played an important role in causing the observed difference between these two tumor types. Thus, their objective in the proposed project has been to analyze the differences in the DNA wrapping of different breast cell types.

Bio:
Dr. Ince received a PhD in pharmacology from Cornell University in 1995. For his thesis work he studied drug resistance in cancer, including regulation of multidrug-resistance (MDR) gene, one of the causes of chemotherapy failure in patients. During this work, he identified a novel non-consensus DNA binding sequence for p53 tumor-suppressor gene in the MDR1 gene promoter that may explain one of the reasons of chemotherapy resistance in p53 mutated tumors.

Following post-doctoral fellowship at Memorial Sloan-Kettering Cancer Center and residency in Anatomic Pathology at Massachusetts General Hospital (2000), he completed a subspecialty fellowship in Women's and Perinatal Pathology at Brigham and Women's Hospital, Harvard Medical School, Boston, MA (2001) where he stayed as a staff pathologist.

Dr. Ince received a 5-year KO-8 mentored physician career development award from National Cancer Institute in 2001 and joined the laboratory of Dr. Robert Weinberg at Whitehead Institute as a visiting clinical scientist the same year. Since then, he has been working on new methods that integrate his background in clinical medicine, molecular biology, pharmacology and pathology, in order to develop better models of breast cancer that mimic the behavior of the human disease such as invasion, metastasis and hormone response in model systems.