Tan A. Ince, MD, PhD

Dr. Ince and colleagues demonstrated that tumors containing identical mutations can have very different outcomes depending on their normal cell-of-origin. These data suggest that the properties of tumor cell-of-origin play a significant role in determining tumor biology. Through their BCRF grant, Dr. Ince's team has identified many different normal breast cell types using molecular markers. These molecular markers were used to confirm that each breast tumor is composed of only one of these cell types. They also found that breast cancer patient outcome and survival changed depending on the cell-of-origin type of their tumor. During the next grant period in 2011-2012, Dr. Ince's team will determine if these molecular markers can be used to develop a better and more detailed cell-type based classification of breast tumors and test different therapies for each new class of breast tumor.

The normal human breast tissue has many different cell types; among these, Dr. Ince and colleagues converted two different normal human breast cell types into ones that can produce tumors (tumorigenic) 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 (BPECs) exhibited the typical features of cancer stem cells and formed tumors in laboratory models when only 10 cells were injected. These cells formed tumors similar to human breast tumors and frequently metastasized to the lungs. In contrast, the tumors derived from another normal breast cell type (HMECs) formed cancer that never spread to other organs and required injection of 100,000 cells to form tumors in the laboratory. Since these cells had the same genes, Dr. Ince and his colleagues concluded that the phenotypic differences of these tumors, including the dramatic difference in the frequency of CSC-like cells, result from epigenetic differences between their different normal cell origins. BCRF support was used towards follow-up studies that expand on this initial work and were designed to describe the histone modification and DNA methylation patterns that are associated with tumor phenotypes and cancer stem cells.

Additional areas of investigation in Dr. Ince's laboratory are examination of heat shock protein (HSP) influence on ovarian and breast tumor stem cell phenotype, development of genetically engineered human malignant lung and ovarian cancer models, analysis of cell origin influence on the phenotype of induced pluripotent stem cells (iPS), and development of culture systems for carcinoid tumors, adenoid cystic carcinoma, ovarian and breast cancers.

Mid-year Progress: The most common type of breast cancer, known as estrogen receptor positive, or ER+, has been the most treatable, usually with anti-estrogen therapies that block the growth-promoting effects of estrogen. Dr. Ince's team recently examined a protein named heat shock factor 1 (HSF1), which helps tumor cells cope with metabolic stresses. By studying tumor samples from 1,841 breast cancer patients, these scientists determined that high HSF1 protein levels are found in tumors of nearly 30 percent of the patients. Importantly, the mortality rate of patients with HSF1-high tumors was doubled compared with patients who have HSF1-low tumors.

In order to confirm these results, Dr. Ince and colleagues examined a second group of breast cancer patients and found HSF1-high tumors correlated with a nearly three-fold increase in mortality in this case. These findings could lead to the development of an additional class of drugs that specifically target HSF1, which could improve survival in this subset of patients. The researchers also hope that these results may lead to a clinical trial to test whether survival rates improve when ER+ patients who express HSF1 receive additional, longer or higher doses of treatment. These results were published in Proceedings of the National Academy of Sciences during the last grant period.

Read more about Dr. Ince's work on HealthCanal.com

Bio:
Dr. Ince is an Associate Professor of Pathology and director of Tumor Stem Cell Division at the Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine. After receiving his MD at Hacettepe University in Ankara, Dr. Ince received a PhD degree in Pharmacology from Cornell University. During this work, he identified a novel DNA binding site for the tumor suppressor protein p53 that regulates human multidrug resistance gene (MDR1), which may contribute to chemotherapy resistance in p53 mutated tumors. Following basic science training at Cornell, he continued his clinical training in Anatomic and Surgical Pathology at Massachusetts General Hospital and completed a subspecialty fellowship in breast and gynecologic pathology at Brigham and Women's Hospital, Harvard Medical School.

Dr. Ince received a career development award from National Cancer Institute for advanced research training in the laboratory of Dr. Robert Weinberg at the Whitehead Institute, Massachusetts Institute of Technology, where he stayed during 2000-07. While at the Whitehead Institute, Dr. Ince developed a new cell culture nutrient medium that is now widely used to grow human breast and ovary cells in the laboratory. This advancement provided the opportunity to directly compare genetically identical tumors that were created from various distinct normal human breast cell types. This work 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.