PA-21-071 for Pathea Bruno to CA260126-01 Identifying a proteomic signature for breast cancer detection in breast milk and serum

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Program Director/Principal Investigator (Last, First, Middle): Darie, Costel C. Supplement Application (PAR-18-714) for Candidate Pathea Bruno Funded parent grant CA260126-01: Identifying a proteomic signature for breast cancer detection in breast milk and serum. Project summary Breast Cancer (BC) in young women (reproductive age, pre-menopausal) is associated with increased mortality, and current methods of detecting BC in this group of women have known limitations. Tools for accurately assessing personal BC risk in young women are needed to identify the women who will benefit the most from earlier intervention. Breast milk provides a noninvasive way to examine the health of the breast. We will apply quantitative proteomics to a unique collection of breast milk samples to determine if there is a group of proteins (proteomic signature) that can be used to detect early breast cancer and predict which women are at increased risk of developing BC. We hypothesize that a set of proteins exist in breast milk that can be used to identify women with BC and women at increased risk of developing BC at a young age. We also hypothesize that the set of proteins, detected in the breast milk, can also be detected in the blood and be used to detect BC in non-lactating women. We will identify and quantify proteomics BC signatures in breastmilk and serum that are both potential diagnostics and also inform on pathways and processes that are dysregulated in BC. In Aim 1, we will employ a Multiple Reaction Monitoring (MRM) approach to develop a quantitation method and then use it to quantify the proteins in the milk (20 vs 20) and serum (50 vs 50) samples of donors with Invasive Ductal Carcinoma (IDC) and matched controls, which were already identified as dysregulated by our lab or in other studies. In Aim 2, we will perform peptidomics analysis of the same milk and serum samples. We will analyze them by 1) nanoliquid chromatography tandem mass spectrometry (nanoLC-MS/MS) and 2) by Matrix Assisted Laser Desorption Ionization mass spectrometry (MALDI-MS). These two methods complement each other. In Aim 3, we will use bioinformatics approaches to investigate both the function of the dysregulated milk & serum proteins and their role in onset and progression of BC. The unique aspects of our study include proteomics analysis of breast milk for assessing BC risk. Translation of the proteomic signature from a local microenvironment (breasts) to a systemic environment (blood) will then allow its use in the detection of BC in non-lactating women. Our proposal can impact several medical and research areas: 1) to prevent BC (primary prevention), 2) to identify what makes the breast susceptible to cancer development, and 3) to identify the biochemical pathways that facilitate BC growth, leading to preventive treatments. This AREA grant will also train an extensive number of undergraduate students and direct them towards careers in biomedical fields. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page