> Research & Grants
> Grants Program
> Research Grants
> Research Grants Awarded
Research Grants Awarded
Modulation Of Erbb2 Tumor Metabolism By Akt
Tumor Cell Biology IV
HER2/Neu/ErbB2 is recognized as an important gene in human breast cancer; HER2/Neu/ErbB2 is amplified and overexpressed in 20-30% of human breast cancer, and expression of ErbB2/HER2/Neu is associated with aggressive tumor behavior, decreased time to clinical relapse, and poor prognosis. Transgenic mice that express either activated Neu/ErbB2, or nonactivated c-Neu/ErbB2 in the mammary gland develop mammary tumors that recapitulate many features of the human disease. Expression of constitutively activated Akt in the mammary gland suppresses apoptosis during involution but does not cause mammary tumors. However, expression of activated Akt accelerates mammary tumorigenesis in the MMTV-Neu mice. Understanding the mechanism(s) by which activated Akt1 accelerated tumorigenesis in the MMTV-ErbB2/Neu model may provide insights into the molecular events underlying tumorigenesis. We hypothesize activated Akt1 alters the physiology of c-ErbB2/Neu-induced mammary tumors resulting in increased glucose transport and elevated aerobic glycolysis. We propose to use magnetic resonance spectroscopy to compare the metabolomic profile of MMTV-ErbB2/Neu tumors with bitransgenic MMTV-ErbB2, MMTV-Akt tumors. We will also test the hypothesis that Akt1 is critical in c-Neu induced mammary tumorigenesis by analyzing tumor formation in MMTV-ErbB2/Neu mice that lack one or both alleles of Akt1. Finally, we hypothesize that GLUT1 is required for Akt to alter the metabolism of c-Neu induced mammary tumors. We will test this hypothesis by eliminating expression of GLUT1 in established ErbB2/Neu-induced mammary tumors using Cre recombinase, and determining the effect upon tumor growth, tumor metabolism, and proliferation and apoptosis of tumor cells. Insights into how Akt may modulate tumor cell metabolism may indicate how Akt can accelerate Neu-dependent tumorigenesis and whether regulation of tumor cell metabolism is important in suppression of apoptosis. These data may also provide insights into new therapeutic approaches tailored to the metabolic profile of specific tumors.
For almost eighty years it has been known that most tumors and tumors cells produce energy in a very inefficient manner called glycolysis. This is in spite of the fact that these cells have the machinery to produce energy in a much more efficient manner by means of energy producing reactions that are based in the mitochondria. Recent studies have suggested that an enzyme called Akt is able to reprogram the energy producing pathways in a normal cell to resemble those in a tumor cell by using stimulating the uptake of the sugar glucose by these cells, and by stimulating the production of energy by the inefficient pathway (by glycolysis). ErbB2/Neu is recognized as an important gene in human breast cancer; HER2/Neu/ErbB2 is amplified and overexpressed in 20-30% of human breast cancer, and expression of ErbB2/HER2/Neu in breast cancer is associated with aggressive tumor behavior, decreased time to reappearance of the tumor after treatment, and shorter time to death of the patient. We wish to determine whether Akt can change which pathways are used to make energy in breast tumors in mice by comparing the metabolism of a mammary tumor caused by the ErbB2/Neu oncogene in transgenic mice, with the metabolism of a tumor that expresses both activated Akt and the ErbB2/Neu oncogene. We hypothesize that activated Akt1 will alter the physiology of ErbB2/Neu -induced mammary tumors, resulting in increased sugar (glucose) transport into the cell, and production of energy by the inefficient pathway (glycolysis). We will use magnetic resonance spectroscopy to compare the metabolism of these two different types of tumors. We will also eliminate the expression of Akt1 from mice to see if this alters the ability of ErbB2/Neu to produce breast tumors in mice. Finally, we will test whether a sugar transporter called GLUT1 is required for Akt to alter the metabolism of the ErbB2/Neu breast tumors by eliminating expression of GLUT1 in established ErbB2 mammary tumors in mice using a technique call tissue-specific recombination. If we can learn how Akt can alter the energy producing reactions in a tumor, we may be able to use this information to determine how to tailor new therapies to kill tumor cells based upon their different physiology. One may also learn how nontraditional approaches to treatment of tumors, including diet and nutritional supplements, may be used to alter the growth of tumor cells.