Advances in sequencing and associated bioinformatic analyses are allowing unprecedented insight into how breast cancers become drug resistance and progress to metastasis. We are analyzing breast cancer progression by sequencing patient-matched pairs of tumor biopsies (primary and metastasis), longitudinal circulating tumor DNA (ctDNA) and post-mortem tissue. Through this program we have identified numerous gained attributes in metastatic disease with some of these representing potential therapeutic opportunities. In this talk I will summarize our work to date in this area.
Environmental epigenetics to fight breast cancer risk and development
The multifactorial origin of cancer is associated with the build-up of epigenetic changes that ultimately push cells into the cancer spiral. The underlying mechanisms involve environmental exposure-mediated alterations in the microenvironment of cells. Exosomes and free molecules, like reactive oxygen species, are likely contributors to the microenvironmental impact on the epigenome, in addition to physical constraints. A major issue in prevention is to identify worthwhile biological risk markers of a particular cancer that may also be early indicators of the success of a preventive intervention. Another issue is to revert the risk by targeting the appropriate epigenetic pathways, with methods that include as little as possible disadvantage for the patient. These are some of the goals of the transdisciplinary International Breast Cancer & Nutrition (IBCN) Project. I will present collaborative approaches to identify epigenetic markers of risk that combine different risk populations and in vitro risk-on-chip (ROC) models. The ROC can be tailored to specific microenvironmental conditions of human tissues. Results will be discussed in the context of the accelerated aging of tissues and the modulatory effect of nutrition on the exposome.
Polypharmacology of botanical extracts: Is there a link to breast cancer prevention?
Breast cancer is the most frequently diagnosed cancer occurring in women in Germany with almost 72.000 cases diagnosed in 2013 and an expected increase to 77.000 cases in 2020. It is unquestionable that estrogens play a pivotal role in the development of breast cancer, as about 70 % of all breast cancers cases are estrogen dependent, with four major mechanisms contributing to estrogen-dependent mammary gland carcinogenesis and breast cancer growth. These are the hormonal, the chemical, the inflammatory, and the epigenetic pathway. Consequently, inhibition of any of these pathways may result in breast cancer prevention. So far, we focused on the hormonal pathway, which plays a key role in tumor promotion by estrogenic compounds through an estrogen receptor-α (ERα) dependent mechanism. While conventional therapies focus on the inhibition of synthesis of the ligand E2 or on inhibition of its function on the ERα by receptor antagonists, we hypothesize that the polypharmacological nature of botanical extracts may functionally inhibit ERα by simultaneously activating additional/alternative pathways, which in turn functionally inhibit ERα mediated effects. Those pathways comprise the ERβ signaling and the arylhydrocarbon receptor (AhR) signaling pathway. The examples provided here suggest that activation of the ERβ- or the AhR-signalling pathways by non-toxic, plant-derived agonists may represent a preventive strategy for hormone dependent mammary gland tumors.
Targeting ErbB-2 nuclear function induces the interferon signalling pathway in breast cancer
ErbB2, a member of ErbB family of receptor tyrosine kinases, is an oncogenic driver in breast cancer (BC). Despite clinical efficiency of ErbB2-targeted therapies (trastuzumab) resistance to drugs is a major issue. ErbB2 is a membrane-bound receptor, but also migrates to the nucleus (NErbB2) to act as a transcription factor/coactivator. We reported the paramount importance of NErbB2 in TZ-resistant BC; now we used a TZ-resistant model with high basal NErbB2 levels to explore its induced transcriptome. RNAseq was run on JIMT1 cells transfected or not with an ErbB2 nuclear localization domain mutant which is also a dominant-negative inhibitor of endogenous NErbB2 migration. Exclusion of NErbB2 modulated the expression of nearly 300 genes. Functional analysis revealed that NErbB2 blockade enriched the expression of genes involved in type-I interferon signaling pathway. IFNB1, OAS2 and TRIM22 were among the top modulated genes. In independent validation experiments blockade of NErbB2 induced expression of these genes in different models of BC. In vivo experiments demonstrated that blockade of NErbB2 significantly inhibits tumor growth and induced mRNA expression of these genes. ChIP assays revealed recruitment of ErbB2 onto IFNB1 coding and promoter regions in normal growth conditions. These results reveal the repression of the type-I interferon pathway as a mechanism of carcinogenesis in ErbB2positive BC and essentially highlight NErbB2 as a therapeutic target in TZ-resistant BC.
