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    Research Grants Awarded

    Mammary Stem Cells And Proteomic Biomarkers Of Benign Breast Disease: Molecular Tools To Improve Breast Cancer Risk Prediction.

    Grant Mechanism:
    Postdoctoral Fellowships

    Scientific Abstract:
    The increased use of mammography screening has made it possible to detect early proliferative changes in the breast, leading to the emergence of benign breast disease (BBD) as an important therapeutic and diagnostic challenge. However, the heterogeneous nature of the disease, limited understanding of the biological importance of the spectrum of BBD lesions, and lack of accurate molecular-based risk categories hinders the ability to diagnose and assign prognostic significance to biopsy findings. A number of epidemiologic studies provide evidence for a significant relationship between BBD lesions and subsequent risk of developing breast cancer. To date the earliest recognizable precursor of invasive carcinoma of the breast is atypical ductal hyperplasia (ADH), the diagnosis of which is based on pathological criteria. Although ADH is cytologically atypical and architecturally more complex than usual ductal hyperplasia (DH), it still does not have the features necessary for the diagnosis of ductal carcinoma in situ. Emerging data support the hypothesis that ?histologically normal? breast epithelial cells from healthy women already contain genetic and epigenetic alterations, which render them more susceptible to malignant transformation. However, the definition of ?histologically normal? can vary among pathologists. Furthermore, molecular markers able to identify ADH, DH, non-proliferative fibrocystic lesions, and sclerosing adenosis from otherwise morphologically normal breast epithelial cells remain largely unknown. The objective of the proposed studies is to establish proteomic markers that can identify subtypes of BBD and distinguish breast tissue at high-risk for neoplastic progression. Preliminary data evaluating two candidate markers indicated that subpopulations of cells within BBD lesions uniquely expressed these proteins, which in turn were differentially expressed within the various subtypes of infiltrating ductal carcinoma, i.e., luminal A, B, basal, and HER2. In fact, their expression patterns are reminiscent of some recently reported studies of markers identifying cancer stem cells. Indeed, cancer stem-like cells have been isolated from several tissues, including breast carcinoma, and are characterized by their capacity to initiate and maintain tumor growth. Like normal mammary stem cells, breast cancer stem cells are identified by several markers, including a CD44+/CD24-/low phenotype, musashi-1, ALDH1, and co-expression of K14 and K19. These cells have been shown to be highly tumorigenic, have the capacity to self-renew, and generate phenotypically diverse populations of cells. Based on these observations, the hypotheses are that 1) BBD lesions that subsequently progress to breast cancer will express proteins that can be used as biomarkers to help refine breast cancer risk and 2) the number of cells with stem cell-like features will increase within the BBD lesions that progress. To address these concepts, I propose the following Specific Aims: 1. Establish proteomic markers that can identify subtypes of BBD and distinguish breast tissue at high-risk for neoplastic progression. 2. Evaluate IHC expression of candidate biomarkers in conjunction with putative mammary stem cell and tumor stem cell markers (e.g., ALDH1, Ki-67, K14 and K19) to determine if tumor stem cells are present within ?at-risk? BBD lesions. 3. Perform a validation study of the top markers on a larger cohort of patient samples to establish their overall predictive value for breast cancer risk. Overall, identifying biomarkers that can better define subtypes of benign breast disease, and thereby distinguish breast tissue at increased risk for neoplastic progression has clinical implications and merit. The goal is to develop a robust panel of markers that will aid pathologists in their diagnoses and ultimately help establish a measure of future risk. Therefore, this research could help reduce breast cancer incidence and related deaths, if appropriate actions are taken before cancer is diagnosed.

    Lay Abstract:
    Widespread mammography screening has lead to an increase in the number of women who are recommended to have biopsies for suspicious findings on mammograms and in turn more than 700,000 cases of benign breast disease are diagnosed annually. Most benign breast diseases are thought to be harmless, but there is a subset which indicate an increased susceptibility for later breast cancer, or which may even progress to breast cancer themselves. Increasing evidence is accumulating that breast cancers may be derived from a small subset of cells, referred to as tumor stem cells. These cells are characterized by their ability to endlessly self-renew, thereby fueling the growth of the tumor and re-growth after chemotherapy. I believe that some benign lesions may contain these tumor stem-cells as well as other indicators that can aid in identifying those individuals that may have greater likelihood of developing a deadly form of the disease. My concepts are that 1) benign lesions, such as atypical ductal hyperplasia and lobular hyperplasia, the diagnosis of which is based on pathologist opinion that are more likely to progress to breast cancer will express certain types of proteins that can be used as molecular beacons to help refine breast cancer risk, and 2) the number of cells with these stem cell-like features will be increased in number in benign lesions that are most likely to progress to invasive breast cancer. Therefore, the major goal of my studies is to establish a robust panel of biomarkers that can help better identify subtypes of benign breast disease and distinguish breast tissue at high-risk for neoplastic progression. State-of-the-art molecular techniques will be used to establish a number of valuable biomarkers that can identify those individuals at greatest risk of developing invasive disease. Samples of benign breast disease lesions from women that subsequently progressed to cancer will be used to determine which biomarkers have the greatest potential for clinical diagnostic use. Overall, identifying biomarkers that can better define subtypes of benign breast disease, and thereby distinguish breast tissue at increased risk for neoplastic progression has clinical implications and merit. This robust panel of markers that will aid pathologists in their diagnoses and ultimately help establish a measure of future risk. Therefore, this research could help reduce breast cancer incidence and related deaths, if appropriate actions are taken before cancer is diagnosed.