Associate Professor of Pathology
Director, Tumor Stem Cell Division
Interdisciplinary Stem Cell Institute
Miller School of Medicine
University of Miami
Accurate classification is essential to understand the pathophysiology of a disease entity. Hematopoietic malignancies such as leukemias and lymphomas have been successfully classified principally based on the phenotypic similarity between tumor cells vs. normal blood and bone marrow cells. The use of normal cell types as a point of reference to classify tumors, however, has not been widely emulated in solid tumors, partly due to a more limited understanding of normal epithelial cell differentiation in solid tissues compared to the hematopoietic system. To provide a better definition of the subtypes of epithelial cells comprising the normal breast epithelium, Dr. Ince's team performed a systematic analysis of a large set of breast epithelial markers in normal human breast tissue samples. This work resulted in a significantly more detailed description of normal cell types in normal human breast, revealing many more normal breast cell types than previously appreciated. These researchers then applied the information from this analysis to classify human breast tumors into four major subtypes based on their normal cell counterparts. This novel ontological classification scheme is associated with significant patient survival differences among the four breast cancer subtypes and provides actionable insights for personalized treatment of breast tumors with multi-hormone combinations.
In evolutionary biology the ancestory of each species is determined based on key features that are inherited. Using this evolutionary principle, Dr. Ince’s team constructed a tree of life for normal human breast cells, and compared it against 3,157 human breast tumors. They began this study more than 10 years ago with BCRF funding and meticulously started describing normal human breast cell types. Dr. Ince’s research group eventually studied more than 15,000 normal breast cells and discovered eleven previously undefined normal cell subtypes, which were grouped into four new hormonal differentiation groups (HR 0, 1, 2, 3), which were characterized by vitamin D, androgen and estrogen hormone receptor expression.
The researchers found that each patient’s tumor could be placed precisely in this evolutionary tree, and importantly, the patients in different HR groups had different survival rates. Patients with triple HR-positive tumors (HR3) were up to seven times more likely to survive compared to patients with triple HR-negative tumors (HR0). Compared with many existing genetic/molecular tests that uncover 2-3 fold survival differences, this cell-type based approach can become a powerful new tool in predicting patient outcomes. Additionally, description of these HR cell types raises the possibility of cell-targeted therapies; for example with further work these findings could be translated into the clinic as triple hormone therapy for HR3 tumors. Hence, these studies may lead to cell-based diagnosis and treatment options as an alternative to gene-based approaches.
Nearly three-quarters of breast cancers are driven by estrogen. These patients are initially treated with drugs that block estrogen, such as Tamoxifen. However, half of these patients eventually become resistant to this treatment. For these patients and those whose tumors are not estrogen dependent to begin with, there are no alternative hormone treatment options. Dr. Ince’s team found that approximately three-quarters of estrogen-dependent tumors and two-thirds of estrogen-independent tumors expressed hormone receptors for vitamin D and testosterone. They also showed that treatment of breast cancer cells with hormones that activate Vitamin D and testosterone receptors reduced the growth of cancer cells. Also, these hormones increased the defectiveness of standard chemotherapy. With further work these findings may allow using lower doses of chemotherapy with the same effect. Thus, these findings offer the possibility of expanding hormone therapy to patients who are otherwise treated with chemotherapy.
Follow up studies are underway in the laboratory of Dr. Ince in collaboration with other researcher at Sylvester Comprehensive Cancer Center to translate these finding to the clinic. This study was completed in the last grant period and published on January 27, 2014 in the Journal of Clinical Investigation.
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.