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Targeting Fatty Acid Synthase (FAS)-Dependent Endogenous Fatty Acid Metabolism To Prevent Breast Cancer: FAS As A Metabolic Oncogene In Situ Ductal Carcinoma Of The Breast
Tumor Cell Biology V
The main goal of breast cancer therapeutics is to identify and block critical promoters of the sequence normal mammary gland à typical/atypical hyperplastic tissue à in situ carcinoma à infiltrating carcinoma. This proposal is designated to characterize, develop and evaluate both the molecular relevance and the therapeutic value of FAS in DCIS of the breast. FAS, the major enzyme required for the anabolic conversion of dietary carbohydrates to endogenous fatty acids, is minimally expressed in most normal tissues as they appear to utilize preferentially circulating fatty acids for the synthesis of new structural lipids. Conversely, a biologically aggressive subset of breast carcinomas constitutively exhibits FAS overexpression and undergoes significant endogenous fatty acid synthesis. FAS expression is more pronounced in more advanced tumors and it often correlates with a poor prognosis. FAS is also expressed in a small subset of cells in normal breast lobules and terminal ducts whereas, upon development of DCIS, FAS is expressed at higher levels and in a majority of the cells. Considering that higher levels of FAS are expressed in pre-invasive lesions of the breast than in normal tissues, this difference has also the potential for a large therapeutic index to prevent breast cancer. We here envision that: i.) Breast cancer-associated FAS overexpression is determined by the past (development) programming of cells in early-stages of breast carcinomas; ii.) FAS is a “metabolic oncogene” conferring a selective advantage for breast cancer cell proliferation and survival upon stresses such as hypoxia, low pH and/or nutritional deprivation. We suggest that increased FAS gene expression in DCIS represents an indirect, early epiphenomenon, occurring in response to the microenvironment of pre-invasive lesions containing regions of poor oxygenation and high acidity due to, e.g ., lack of angiogenesis. FAS up-regulation in DCIS lesions may represent an obligatory acquisition that selects cells capable to growth and survive upon extracellular biophysical and/or metabolic stresses. The characterization of FAS as a “metabolic oncogene” not only will allow an invaluable adjunct to gene expression profiling or proteomics in the characterization of a sub-set of women at high risk, but it will also reveal that FAS could be exploited as a previously unrecognized molecular target for the chemoprevention and/or the adjuvant treatment of early stage invasive breast cancer.
There is a need to identify targets in early lesions associated with increased risk for the development of breast cancer. New information on the role of “key regulators” of the pre-malignant stages of breast cancer should provide the basis for the development of novel therapies capable to prevent and/or reduce the incidence of breast cancer in women at high risk. This proposal is designated to evaluate the clinical relevance of FAS (Fatty Acid Synthase) in the precursor steps of breast cancer disease such as DCIS. FAS is a cellular “factory” required for the conversion of dietary sugar to fatty acids. In well-nourished individuals, the levels of FAS are very low because most of our tissues make use of the fatty acids derived from dietary fat. On the contrary, after numerous studies, it now appears that a subset of breast carcinomas exhibit gigantic levels of FAS. Importantly, FAS levels are more pronounced in the most aggressive varieties of breast cancer and they often correlate with a poorer prognosis and an increased risk of death. FAS is also expressed in a small subset of normal breast cells whereas, upon development of DCIS, FAS is expressed at higher levels and in a majority of the breast cells. Considering that vastly higher levels of FAS are expressed in precursor lesions of breast cancer than in normal tissues, this difference could be exploited as a valuable target to prevent both the appearance of more advanced breast cancer disease and its spread to distal organs. We here envision that the tight relationship between FAS and the malignant behavior of breast cancer is due to the “past” of cells in the early lesions of the disease. High levels of FAS may confer an advantage to some cells that, with its help, can proliferate and survive upon “stresses” taking place at the beginning of breast cancer development such as low concentrations of oxygen, low pH and/or nutritional deprivation. We suggest that breast cancer-associated FAS is activated in response to the severe environmental conditions which are overcome by the most adapted varieties of breast cancer cells. Therefore, this up-regulation of FAS in early lesions of breast cancer may represent an obligatory “acquisition” selecting an extremely aggressive type of cancer cells capable to growth and spread regardless the environmental situation of the breast. Our proposal will reveal FAS as a new target for the prevention and/or the treatment of breast cancer in women at high risk.