Why are aging and cancer so inherently linked? David Gius, MD, PhD, professor in Radiation Oncology and Pharmacology, studies connections between longevity, cellular processes, and cancer development in an effort to understand the answer to this question.
Specifically, his lab focuses on breast cancer and the sirtuin gene family. These silent information regulator genes affect the lifespan of species in multiple ways. They help cells repair DNA damage that comes with age and suppress tumor development.
Gius joined Feinberg in 2012 from Vanderbilt University. Previously, he served as associate director of the National Institutes of Health Oxford/Cambridge Scholars Program and as chief of the National Cancer Center’s molecular and radiation oncology section. He earned a doctorate degree in molecular genetics from the University of Chicago and his medical degree from Loyola University.
What are your research interests?
A fundamental observation in oncology is that the rate of malignancies increases significantly as a function of age, suggesting a potential mechanistic link between the cellular process governing longevity and the development of cancers. In fact, advanced age is the single most important predictive variable for cancer incidence. However, the genetics and murine models to investigate this idea have not been available.
In this regard, the critical genes in longevity (or aging) have recently been characterized in S. cerevisiae and , and the human homologs are referred to as the sirtuin gene family. It has been hypothesized that sirtuin genes may function as fidelity or repair genes, and that loss or decrease of function, which normally occurs during aging, creates an environment permissive for age-related illness, including cancer. There are several common human solid tumor malignancies that have a very strong statistical connection to increased age, including estrogen positive (ER+) breast malignancies.
Mouse models for hereditary triple-negative breast cancer, which is more common in younger women, have been an instrumental tool for the advancement of our clinical and scientific knowledge to combat this deadly disease. In contrast, there are no or very few physiologically relevant murine models for ER+ breast cancers that are more commonly observed in older women. Thus, it seems logical to assume that breast cancers that develop at a later age are more likely to have a genetic or physiological connection to the cellular processes that govern mammalian aging, including the loss of and/or dysregulation of sirtuin proteins.
To address this idea, over the past five years, we have constructed mice that have the three primary sirtuins genetically deleted. These mice develop ER+ invasive ductal mammary (breast) tumors that have the strongest statistical correlation to increasing age.
What is the ultimate goal of your research?
The overarching goal of my research is to use these novel sirtuin knockout mice as in vivo genetic models to connect aging genes, intracellular aberrant metabolism, and the mechanisms underlying the development of breast cancer.
The mice that lack SirT1 (Wang et al., 2009, Cancer Cell), SirT2 (Kim et al., 2011), and SirT3 (Kim et al., 2010, Cancer Cell) each develop breast cancer, and the levels of SIRT1-3 are also decreased in human breast cancer samples, as compared to normal breast tissues. These mice exhibit altered intracellular and mitochondrial metabolism and develop poorly differentiated ER+ tumors that appear to be very similar to luminal B breast cancers that are commonly observed in older women. Thus, we propose that these murine models can be used to determine the mechanisms for breast cancer development, as well as the identification genetic factors in disease progression. These models would also be used for drug discovery to develop potential new therapeutic strategies for breast cancer.
How does your research advance medical science and knowledge?
One idea of personalized cancer therapy is to identify a specific subgroup of cancer patients that will benefit from specific therapeutic strategy. Murine and human data from our laboratory, started while I was the chief of the molecular radiation biology section at the National Cancer Institute, suggest that there is a subgroup of ER+ luminal B human breast cancer that exhibit partial or complete loss of sirtuin expression. In addition, it appears that roughly 40 percent of all breast cancer patients exhibit a deletion of one of the sirtuin gene, which suggests that loss of these genes may be a key early event in human breast carcinogenesis.
We propose that there are a significant number of women with a sirtuin ER+ breast cancer signature. If correct, this will allow the development of new therapeutic strategies for therapy as well as chemoprevention.
How is your research funded?
My research on breast cancer, which is the primary focus of my laboratory, is funded by two R01 grants from the National Cancer Institute and an Avon Foundation Center of Excellence grant. My laboratory also has an R01 grant to investigate the connection between sirtuins, mitochondrial metabolism, and how human cells respond to cellular stres, including therapeutic irradiation.
Where have you recently published papers?
In 2010, my laboratory published manuscripts in Cancer Cell and Molecular Cell that showed that SIRT3, the mitochondrial sirtuin, is a tumor suppressor protein and functions as a watchdog or fidelity protein to maintain mitochondrial homeostasis. In 2011, we published a manuscript in Cancer Cell showing that the cytoplasmic sirtuin is a tumor suppressor protein, and a letter to the editor in Science.
In 2013, we published a manuscript, which was primarily directed and conducted by Joseph Bass, MD, chief of the Division of Medicine-Endocrinology, that showed those circadian rhythms and the proteins that oversee these rhythms direct mitochondrial metabolism via a mechanism involving SIRT3.
Who are your mentors?
When I first started my graduate education I was very fortunate to have one of the University of Chicago’s best mentors as my thesis adviser. I think it is safe to say I would not be where I am today without his patience and mentorship. In fact, he is now chairman of Microbiology-Immunology at Northwestern University Feinberg School of Medicine, Lou Laimins, PhD.