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Bionergetic Control Of Breast Cancer Growth By The Transcriptional Co Activator Pgc1Alpha
Career Catalyst Research
Increased glycolysis and reduced oxidative phosphorylation are hallmarks of cancer that are associated with increased cancer cell proliferation and survival. In fact, cancer cells depend heavily upon glycolysis, even in the presence of oxygen, a phenomenon known as aerobic glycolysis or the ?Warburg effect?. Thus, expression of glycolytic genes is increased in cancers including breast cancer and expression of key genes involved in oxidative phosporylation (OxPhos) is reduced. While several progrowth molecules are believed to be responsible for the increased glycolysis, the mechanisms of OxPhos downregulation are less well understood. The transcriptional coactivator PG1alpha is an important regulator of OxPhos. Recent studies demonstrate that PGC1alpha expression is reduced in breast cancer. Reduced OxPhos is also associated with reduced PGC1alpha expression in other tumor types. Therefore we hypothesize that PGC1alpha may influence breast cancer cell proliferation and carcinogenesis by regulating OxPhos expression. Moreover, the fact that PGC1alpha expression is inducible suggests that it is an excellent target for therapeutic intervention in breast cancer. Therefore we will evaluate the role of PGC1alpha on breast cancer cells by the following specific aims: i) Determine the relationship between PGC1alpha and OxPhos gene expression in human breast tumors, ii) Define the role of PGC1alpha in cancer cell metabolism, growth, and survival and iii) Directly test the ability of PGC1alpha to inhibit breast tumor growth. Identifying a role for PGC1alpha in breast cancer growth will increase our understanding of breast cancer biology and the ability to target tumor bienergetics, via PGC1alpha, as a potential cancer therapy.
The ability of a normal cell, let alone a tumor cell, to derive energy from nutrients is crucial for its survival. In the presence of oxygen, normal cells typically derive their energy from the powerplants with in the cell mitochondria through a process known as oxidative phosphorylation. In the absence of oxygen, cells can also generate energy from the breakdown of the sugars by a process known as glycolysis. Although oxidative phosphorylation is more efficient and produces more energy than glycolysis, glycolysis can produces energy more rapidly. Interestingly, the Nobel Laureate Otto Warburg observed over 80 years ago that tumor cells typically derive a majority of their energy from glycolysis even in the presence of oxygen, a term called aerobic glycolysis or the ?Warburg Effect?. This makes sense since tumors cells are rapidly dividing and need a rapid energy source. In addition glycolysis provides many intermediates that a growing tumor cell needs to develop.
Studies have shown that the increase in glycolysis observed in tumors is a result of an increase in many of the molecules that carryout glycolysis. In addition, studies have shown a reduction in the expression of many of the molecules that carry out oxidative phosphorylation. Importantly, inhibiting glycolysis and increasing oxidative phosphorylation can inhibit cancer cell growth. We are studying a molecule called PPARgamma Coactivator 1 alpha (PGC1alpha). PGC1alpha plays a crucial role in nutrient sensing and regulation. Regulation of oxidative phosphorylation is controlled in large part by PGC1alpha. Data from our lab as well as others, shows that the levels of PGC1alpha are reduced in tumors. This provides a strong link between reduced oxidative phosphorylation and reduced PGC1alpha. Importantly, PGC1alpha expression and activity are induced by drugs that are clinically approved for other diseases (and relatively non-toxic) and by dietary factors as well. In addition, exercise and reduced calorie intake increase PGC1alpha levels. These are physiological conditions that are known to reduce the incidence of breast cancer. In addition, obesity decreases the levels of PGC1alpha. Obesity has been associated with increased breast cancer risk in post-menopausal women. With the connection between PGC1 and cancer, and the fact that levels and activity of PGC1 can be induced, has prompted us to study the connection between PGC1 and cancer as a target for breast cancer therapy. We are going to do this by examining the relationship between the the expression of oxidative phosphorylation genes and PGC1alpha in human breast tumors. We will then engineer breast cancer cells to overexpress PGC1 and study the effects of cell proliferation. We will also use a drug that has been shown to increase the activity of PGC1alpha and examine the effect on cell growth. This would be significant since the drug, metformin, is already clinically approved for diabetes, has a relatively good toxicitiy profile, (especially when compared to the standard chemotherapy regimen). This would hasten its implementation in the clinic if our results are positive. We will then directly test whether PGC1alpha expression and activity play a role in breast cancer development and proliferation. The ability to increase PGC1alpha activity and expression with compounds that are already available suggests it may be possible to target PGC1alpha in the near future. Furthermore, the fact that PGC1alpha can be induced by diet and exercise will provide breast patients with a rationale to take a more active role in management of their own disease, in partnership with their physician, by focusing on factors that they may be able to control directly.