Prognostic Implications of DNA Glycation in Breast Cancer
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: Early detection of breast cancer is the key to a successful clinical outcome. The current detection arsenal for breast cancer suffers from the limitation that tumor formation in the earliest stages often goes unnoticed. Improvement in detection requires a highly specific and sensitive technique and a biochemical marker (biomarker) that can be observed at low levels. In order to be considered an ideal biomarker, the presence of the species must correlate with the initiation, progression, and metastasis of the cancer. Cancer is caused by direct damage to the DNA whether it is from environmental carcinogens such as cigarette smoke or UV rays or from sources that are generated within our cells such as free radicals or dysfunctional genes that have been inherited. This damage can result in mutations in the DNA sequence that can lead to deregulation of cellular function. Within the cancer field, there is renewed interest in exploiting the profound metabolic differences between normal and cancer cells, specifically the shift to an alternative energy pathway which is characteristic of many cancers. This energy shift was first observed in cancer over 70 years ago and is referred to as the Warburg effect. We now know that it creates reactive by-products that can damage DNA. We have chosen to focus our research on a specific DNA adduct, CEdG, which results from an individual building block of DNA reacting with toxic metabolites that accumulate in cells experiencing the Warburg effect, and to determine if this may be used as a diagnostic biomarker for breast cancer.
 
 
 
 
 
 
 
 The central hypothesis of this proposal is that elevated CEdG levels correlate with the progression of breast cancer. Clinical studies using an imaging technique known as positron emission tomography (PET) has established that breast cancers displaying the Warburg effect have lower overall survival, lower recurrence free survival and increased incidence of metastasis to the lymph nodes. Though informative, the patients enrolled in the studies had already developed tumors of significant mass in order to have been detected by PET. A more sensitive test along with a biomarker that correlates with the metabolic shift will allow for diagnosis at a much earlier stage of tumorigenesis. Our preliminary data has detected levels of CEdG in human breast tumors and further studies proposed herein will shed light on its suitability as a predictive biomarker and its role in breast tumor progression.
 
 
 
 
 
 
 
 This proposal sets forth a novel analytical chemistry approach to quantitate the DNA adduct, CEdG. The advantage of this technique is that it is extremely sensitive and specific. We have established the presence of CEdG in cryopreserved breast tumor and normal breast tissue from the City of Hope tumor bank, which provides a wealth of biopsy samples that have been collected from a wide range of patient backgrounds including under-represented minorities. Our next step is to use breast cancer patients’ urine and blood for CEdG measurement. We have commenced in vitro biochemical studies to determine what effect CEdG has on the rate of DNA replication and mutagenesis. The techniques for measuring these biochemical effects have been established in our lab during previous studies of free radical and lipid oxidation mediated DNA damage.