Mortality in breast cancer, the most common malignancy in women, is usually caused by metastatic disease. This application focuses on the impact of changes in lactic acid metabolism on disease evolution, progression and development of metastases. This application focuses on two components of an abnormal metabolic phenotype in breast cancer involving lactate dehydrogenase A (LDH-A) and monocarboxylate transporter 4 (MCT4), because LDH-A is a bridge between several metabolic pathways and MCT-4 is primarily involved in the export of lactate from cancer cells. We propose to show that cells and tumors with high lactate secretion and/or tissue concentrations express high levels of LDH-A and MCT4, and that they are prone to be more invasive and to develop metastases. The expression of LDH-A and MCT4 are very highly correlated with the duration of metastasis-free survival in human breast cancer, and expression of these genes is expected to be highly correlated with tumor lactate concentrations. In addition, the product of LDH-A activity (lactate) can be assessed non-invasively and quantitatively using magnetic resonance spectroscopic (MRS) imaging (MRSI). Although lactate MRSI is not a new technique, the correlation with LDH-A and MCT4 gene expression and the non-invasive monitoring of LDH-A targeted therapy using lactate MRSI is novel. This research focus is supported by our expression profile analysis of genes involved in lactate metabolism in human breast cancer (see Fig. 1, Section 3.1), and strongly supports the rationale for this proposal. Our hypotheses are: 1) tumor lactate levels can be quantitatively assessed by MRSI;2) tumor lactate levels will reflect corresponding levels of LDH-A and MCT4 expression, 3) tumor lactate, LDH-A and MCT4 are important components of the metabolic phenotype and have a major impact on the tumor microenvironment, tumor progression and the development of metastases;and 4) LDH-A inhibition can reduce breast cancer progression and reduce the development of metastases.
Our Aims are: 1) Identify the associations between LDH-A, MCT4, lactate production, and the aggressive/ metastatic tumor phenotype in different orthotopic and transgenic models of breast cancer during tumor progression;and 2) Image and monitor the effects of LDH-A silencing/knock-down and determine the effect of lactate and pHe levels on tumor growth and development of metastases.
Mortality in breast cancer, the most common malignancy in women, is usually caused by metastatic disease;and changes in tumor metabolism are known to occur as the tumor evolves into a more aggressive, metastatic- prone state. This application focuses on specific metabolic alterations in breast cancer and explores the impact of changes in lactic acid metabolism on disease evolution, progression and the development of metastases. We will show that inhibition of LDH-A expression, an important metabolic enzyme in human breast cancer, reduces tumor progression and the development of metastases in animal models;and that the risk of developing metastases and the response to LDH-A targeted therapy can be imaged non-invasively with MRSI.
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