Gordon B. Mills, MD, PhD

2012-2013 BCRF Project:
Lifestyle is a fundamental component of the complex process that leads to many human diseases, including cancer. Importantly, the combination of excessive calorie intake and a lack of exercise, which result in weight gain and obesity, represent a strong risk factor for the development of breast cancer, mainly in postmenopausal women. For this reason, the existing spreading of the obesity epidemic in the United States and elsewhere in the world will require an intense effort by the medical and research community to prevent the rise of obesity-related breast cancers in the years to come.

At the moment, the pathophysiological and molecular mechanisms that are responsible for the link between obesity and breast cancer remain poorly understood and are the object of intense scientific investigation. Lysophosphatidic acid (LPA) signaling is now emerging as an important regulator of cell metabolism and obesity predisposition. It has been recently recognized that LPA is a lipokine with modulatory activity toward adipocyte differentiation, fat accumulation, and energy expenditure. Dr. Mills has demonstrated that laboratory models expressing autotaxin (ATX), the enzyme that produces LPA, demonstrate a propensity to obesity. This is of importance because of the central role that metabolism plays in cancer biology. This preclinical breast cancer model developed by Dr. Mills's team represents a unique research tool because tumor formation is spontaneously induced by an increased production and/or signaling activity of LPA. Thus, as a complementary extension of previous studies, Dr. Mills will continue to investigate the effect that diet and fat development have in the formation and progression of tumors.

Mid-year Progress: During the previous BCRF funding periods, Dr. Mills's laboratory established a novel model of breast cancer that is driven by an increased production and activity of lysophosphatidic acid (LPA) in the epithelial cells of mammary glands. They have now established a tumor transplantation procedure by which fragments dissected from these tumors are passaged in mammary glands of recipient mice. This approach is proving to be a versatile and pathophysiologically relevant experimental system that allows the researchers to study breast cancer origin and progression in different contexts. Dr. Mills's group has observed that these tumors, despite sharing a common origin, are characterized by various degrees of aggressiveness. They have begun to explore the effects that diet and weight gain play in breast cancer development and progression. They are also presently testing different dietary combinations and treatment intervals to understand how dietary changes and fat intake affect tumor progression and natural behavior of breast cancer by reshaping molecular networks and metabolic parameters both in the tumor and the host. The ultimate goal of this research is to acquire a deeper understanding of the mechanisms that drive malignant growths in the breast and to pave the way to innovative treatments and a better informed clinical practice.

Bio:
Dr. Mills earned his MD and his PhD in biochemistry from the University of Alberta. From 1985 to 1994, Dr. Mills was a member of the faculty of the University of Toronto, rising to the rank of Associate Professor in the departments of Obstetrics and Gynecology, Immunology, and Clinical Biochemistry. He was an active staff member and director of Oncology Research at the Toronto Hospital during this time.

In 1994, Dr. Mills was recruited to The University of Texas MD Anderson Cancer Center, where he holds the rank of professor with joint appointments in Systems Biology, Breast Medical Oncology and Immunology; serves as chairman of the Department of Systems Biology; head of the section of Molecular Therapeutics and holds the Ann Rife Cox Chair in Gynecology. Dr. Mills is co-Director of the Kleberg Center for Molecular Markers and director for the Gita and Ali Saberioon Molecular Markers building.

With more than 300 publications, Dr. Mills has authored papers in such prestigious journals as Nature, Cell, Oncogene, Nature Genetics, Nature Medicine, Nature Cell Biology, Nature Cancer Reviews, Cancer Research, Proceedings of the National Academy of Sciences and Clinical Cancer Research. A testament to the quality of his research, Dr. Mills' work in ovarian cancer, breast cancer and tumor immunology has been continuously funded by major peer-reviewed grants for over 20 years. He serves as principal investigator or project investigator on ten national peer review grants including NIH/NCI SPOREs and PPGs, Department of Defense, and Komen Foundation grants, and collaborator on multiple other national peer-reviewed grants.

Dr. Mills has made significant contributions to the understanding of ovarian tumorigenesis, including the identification and development of lysophosphatidic acid (LPA) and sphingosine 1 phosphate (S1P) as possible markers for early-stage ovarian cancer and as a potential targets for therapy. He also has played a major role in increasing our understanding of the genetic aberrations in the phosphatidylinositol 3 kinase/PTEN/AKT pathway, forwarding this cascade as a major target for the therapy of multiple types of cancer. Dr. Mills has also extensively explored the genomics and genetics of ovarian and breast cancer identifying and characterizing a number of potential oncogenes and tumor suppressor genes including ARHI, Rab25, EVI1 and PKCi. These are being explored both as markers and targets for therapy.

Dr. Mills is the holder of more than 20 patents related to novel technologies and molecular markers. He was a co founder of an early diagnostics company. He currently sits on the scientific advisory boards of multiple different companies and venture capital groups. Based on his expertise in technology development, he is the head of the MD Anderson Cancer Center Technology Review Committee.

Dr. Mills now heads the Kleberg Center for Molecular Markers. This Center holds the responsibility for developing personalized molecular medicine at the MD Anderson Cancer Center. Specifically, this center will implement a series of novel technologies to for the first time explore the genetic changes and their consequences at the DNA, RNA and protein levels in human tumors. This information will be used to identify patients at high risk for tumor development so they can be triaged to early screening and chemoprevention, identify markers to use in early screening, and to determine approaches to ensure that patients receive the most effective and least toxic therapies targeting the underlying genetic aberrations in tumors.

Dr. Mills is the inaugural chair of the Department of Systems Biology. The mission of the Department of Systems Biology to understand how a process, a cell, a group of cells, or an organism works at a global level and how different components of the process cooperate to attain the "correct" functional outcome. It is now recognized that component-by-component analysis is not sufficient for the study of signal transduction, gene regulatory and biochemical networks, oncogenic transformation, and other processes in which many genes and proteins interact. Understanding the dynamics of such systems, both qualitatively and quantitatively, and constructing mathematical models with robust predictive capabilities will be necessary for the realization of the promise of personalized molecular medicine and the efficient implementation of targeted therapeutics.