Novel Markers for Disease Outcome in Breast Cancer

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

Project 1: We continued to comprehensively examine the metabolome, proteome, and transcriptome of breast tumors from African American and European-American patients for biomarker discovery. The promise of this approach is the discovery of markers for prognosis, and of mechanisms that may drive the aggressiveness of breast cancer in African American women. We characterized the metabolomic profile of breast tumors and adjacent non-cancerous tissue from 67 patients and described the differential abundance of more than 200 metabolites. One of them was 2-hydroxyglutarate, which was elevated up to 100-fold in tumors that were primarily estrogen receptor-negative. This accumulation of 2-hydroxyglutarate was closely associated with the co-occurrence of a c-Myc signaling signature in the tumors (PMID: 24316975). In a follow up study, we could show that breast tumors predominately accumulate D-2-hydroxyglutarate and describe the D-2-hydroxyglutarate-producing alcohol dehydrogenase, iron-containing protein 1 (ADHFE1) as a breast cancer oncoprotein that is associated with disease survival. Our data show that ADHFE1 promotes a reductive glutamine metabolism with increased D-2-hydroxyglutarate and mitochondrial reactive oxygen species formation (PMID: 29202474). In an extension to these metabolome studies, we analyzed breast tumors for presence of bile acids and how their accumulation may relate to breast cancer biology. This exploratory analysis revealed that a subset of breast tumors accumulates bile acids and show a distinct tumor biology. Tumors with a high bile acid content showed a decreased proliferation rate and associated with improved survival (PMID: 31296531). In a different study, focusing on the breast cancer proteome, we performed an integrated proteotranscriptomic characterization of breast tumors. We measured global proteome and transcriptome expression in 118 human breast tumors and adjacent non-cancerous tissues. Comparing proteome with transcriptome data, we found that the proteome describes differences between cancerous and non-cancerous tissue that are not captured by the transcriptome. Moreover, the proteome and transcriptome highlighted partially different tumor biologies. When we applied an integrated analysis of both technologies, the approach revealed a global increase in protein-mRNA concordance in tumors. Highly correlated protein-gene pairs were enriched in protein processing and disease metabolic pathways and occurred more commonly in tumors of African American patients. The increased concordance between transcript and protein levels was further associated with aggressive disease, including basal-like/triple-negative tumors, and decreased patient survival. Our study indicates that an integrated analysis of the proteome and transcriptome in cancer can uncover disease characteristics beyond the ability of a single technology. These data have been published in 2018 (PMID: 30501643). Project 2: Environmental exposures and obesity can modify DNA methylation patterns and alter the tumor epigenome, as shown for prostate and breast cancer. Our current research investigates genome-wide DNA methylation in human breast tissues in association with age, body mass index, tissue inflammation, population group, and neighborhood deprivation measures. Here, we are combining the resources from the NCI-Maryland contract resource with a complementary resource acquired by the Gierach laboratory (DCEG/NCI) from the Komen tissue bank. This partnership will encompass genome-wide DNA methylation data from about one thousand women. It is the unique aspect of the NCI-Maryland cohort that we can link DNA methylation pattern to the neighborhood deprivation index, breast cancer, and the diagnosis of diabetes in this population. The Komen tissue bank cohort consists of African American and European American age-matched, pre-menopausal donors without breast cancer. These women provided non-cancerous breast tissue from breast reduction surgery. We will study DNA methylation and tissue inflammation markers in these tissues, additional breast reduction tissues from the NCI-Maryland cohort, and in normal breast tissues obtained from autopsy cases. This study will be supplemented with DNA methylation data from breast tumor-adjacent non-cancerous tissue pairs from African American and European American patients. It is the main aim of this collaboration to evaluate patterns of genome-wide DNA methylation in association with tissue inflammation markers like crown-like structures and other risk factors, differences between African American and European-American women, the impact of diabetes and neighborhood deprivation measures on DNA methylation, and to study differences between cancerous and non-cancerous tissues in African American and European-American women. The DNA methylation data can also be integrated with existing gene expression data sets for many of these tissues. Project 3: This project evaluates the role of environmentally induced stress signaling and co-morbidities in breast cancer progression. We started projects studying the impact of stressful life events and diabetes on tumor biology. In a clinical study, we will give breast cancer patients, who are scheduled for breast cancer surgery, a short survey evaluating their perceived stress and social isolation. We will also collect frozen tumor and adjacent normal breast tissue and blood samples from these patients and evaluate whether the breast tissue or the blood samples have a biological signature related to their perceived stress and social isolation status. We hypothesize that patients with a high perceived stress exposure have a biological signature consistent with a more aggressive disease and poorer survival. The pilot study is designed to collect 100 tumor/normal pairs from consented patients with a completed survey. In a second study, we are evaluating the relationship between self-reported diabetes and tumor biology and breast cancer aggressiveness. Here, a patient's diabetes status based on survey and medical record data will be correlated with global gene expression, metabolite patterns, and mutational signatures in their tumors to identify cancer-related pathway that are impacted by diabetes. This study is ongoing and will assess whether type 1 and 2 diabetes induce changes to tumor biology that enhance the odds of disease progression. We are particularly interested in changes to metabolic pathways, and how they can be targeted to decrease the negative impact that a diabetes diagnosis may have on breast cancer outcomes. More specifically, we are investigating the influence of diabetes on breast cancer biology using a three-pronged approach that includes analysis of orthotopic human tumor xenografts, patient tumors, and breast cancer cells exposed to diabetes/hyperglycemia-like conditions. Current findings are as follows: Diabetes did not enhance cell proliferation but induced mesenchymal and stem cell-like phenotypes linked to increased mobility and odds of metastasis. It also promoted oxyradical formation and both transcriptome and mutational signatures of DNA repair deficiency. Moreover, food- and microbiome-derived metabolites tended to accumulate in breast tumors in presence of diabetes, potentially affecting tumor biology. Breast cancer cells cultured under hyperglycemia-like conditions acquired increased DNA damage and sensitivity to DNA repair inhibitors. Based on these observations, diabetes-associated breast tumors may show an increased drug response to DN *TRUNCATED*