Breast cancer is among the most common non-skin cancers and the major cause of cancer-related death in women worldwide. A small subpopulation of men is diagnosed with breast cancer each year. Breast tumors arise from epithelial cells of the milk ducts and are classified into ductal or lobular carcinomas based on histology. According to their molecular characteristics, breast cancers can be further classified by their differentiation state and gene expression profiles into luminal and basal subtypes and the expression of estrogen (ER), progesterone (PR) and human epidermal growth factor receptor (HER2). Molecular categorization into ER+ (70%), HER2+ (20%) or triple negative breast cancers (TNBC; 10%, HER2-PR-ER-) has significant implication into the choice of treatment modalities such as anti-hormonal or HER2-targeted therapies; currently, there is no targeted therapy for TNBC available, and the development of improved therapies for TNBC has the highest priority in breast cancer research as TNBC show only a poor response to standard chemotherapy.
The intertumor heterogeneity is reflected in the genetic landscape of breast cancers: although mutations in the p53 gene, activating mutations in PI3K signaling as well as MAPK signaling are commonly mutated in the breast cancer subtypes, TNBCs show the highest rate of p53 mutations and HER2+ luminal breast cancers are characterized by amplification or overexpression of the ERBB2 gene. Breast cancer research aims to identify the source of both, inter- and intra-tumor heterogeneity to improve diagnostics, biomarker selection and treatment decisions. It is becoming clear that the cell of origin together with the initial genetic event contribute to the generation of distinct tumor subtypes, yet, tumor phenotypes do not predict the cell of origin of cancer (as basal-like subtypes can arise from luminal progenitors) and genetic events can induce reprogramming into distinct subtypes.
Another hot topic in breast cancer research is the temporal course of metastasis and recurrence. Breast cancers metastasize to the bone, lungs, liver and brain, and breast cancers often recur after a long period of time as metastatic disease and more than 60% of breast cancer death occur more than 5 years after initial diagnosis. This phenomenon my be explained by different aspects of tumor biology, whereas in some breast cancer subtypes tumor cells may have a very slow doubling time, leading to slow growth kinetics of the primary as well as the disseminated tumor cells and consequently, late detection of metastatic lesions. Another possible explanation is tumor dormancy, in which disseminated cancer cells may enter cellular quiescence to endure in hostile microenvironments until appropriate signals allow these cells to resume malignant growth. Disseminated tumor cells can be detected in the bone marrow of breast cancer patients years after the removal of the primary tumor and these cells are characterized by a quiescent phenotype, accompanied by activated stress signaling (e.g. UPR).
TICC Faculty who are involved in breast cancer research:
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