Resistance to paclitaxel is associated with a variant of the gene BCL2 in multiple tumor types.

Paclitaxel, the most commonly used form of chemotherapy, is utilized in curative protocols in different types of cancer. The response to treatment differs among patients. Biological interpretation of a mechanism to explain this personalized response is still unavailable. Since paclitaxel is known to target BCL2 and TUBB1, we used pan-cancer genomic data from hundreds of patients to show that a single-nucleotide variant in the BCL2 sequence can predict a patient's response to paclitaxel. Here, we show a connection between this BCL2 genomic variant, its transcript structure, and protein abundance. We demonstrate these findings in silico, in vitro, in formalin-fixed paraffin-embedded (FFPE) tissue, and in patient lymphocytes. We show that tumors with the specific variant are more resistant to paclitaxel. We also show that tumor and normal cells with the variant express higher levels of BCL2 protein, a phenomenon that we validated in an independent cohort of patients. Our results indicate BCL2 sequence variations as determinants of chemotherapy resistance. The knowledge of individual BCL2 genomic sequences prior to the choice of chemotherapy may improve patient survival. The current work also demonstrates the benefit of community-wide, integrative omics data sources combined with in-lab experimentation and validation sets.

hsa-miR-9 controls the mobility behavior of glioblastoma cells via regulation of MAPK14 signaling elements.

BACKGROUND: Glioblastoma Multiforme (GBM) is the most common and lethal primary tumor of the brain. GBM is associated with one of the worst 5-year survival rates among all human cancers, despite much effort in different modes of treatment. RESULTS: Here, we demonstrate specific GBM cancer phenotypes that are governed by modifications to the MAPAKAP network. We then demonstrate a novel regulation mode by which a set of five key factors of the MAPKAP pathway are regulated by the same microRNA, hsa-miR-9.We demonstrate that hsa-miR-9 overexpression leads to MAPKAP signaling inhibition, partially by interfering with the MAPK14/MAPKAP3 complex. Further, hsa-miR-9 overexpression initiates re-arrangement of actin filaments, which leads us to hypothesize a mechanism for the observed phenotypic shift. CONCLUSION: The work presented here exposes novel microRNA features and situates hsa-miR-9 as a therapeutic target, which governs metastasis and thus determines prognosis in GBM through MAPKAP signaling.

Shift in GATA3 functions, and GATA3 mutations, control progression and clinical presentation in breast cancer.

INTRODUCTION: GATA binding protein 3 (GATA3) is a regulator of mammary luminal cell differentiation, and an estrogen receptor (ER) associated marker in breast cancer. Tumor suppressor functions of GATA3 have been demonstrated primarily in basal-like breast cancers. Here, we focused on its function in luminal breast cancer, where GATA3 is frequently mutated, and its levels are significantly elevated. METHODS: GATA3 target genes were identified in normal- and luminal cancer- mammary cells by ChIP-seq, followed by examination of the effects of GATA3 expressions and mutations on tumorigenesis-associated genes and processes. Additionally, mutations and expression data of luminal breast cancer patients from The Cancer Genome Atlas were analyzed to characterize genetic signatures associated with GATA3 mutations. RESULTS: We show that some GATA3 effects shift from tumor suppressing to tumor promoting during tumorigenesis, with deregulation of three genes, BCL2, DACH1, THSD4, representing major GATA3-controlled processes in cancer progression. In addition, we identify an altered activity of mutant GATA3, and distinct associated genetic signatures. These signatures depend on the functional domain mutated; and, for a specific subgroup, are shared with basal-like breast cancer patients, who are a clinical group with regard to considerations of mode of treatment. CONCLUSIONS: The GATA3 dependent mechanisms may call for special considerations for proper prognosis and treatment of patients.

SENP5 mediates breast cancer invasion via a TGFßRI SUMOylation cascade.

Identifying novel mechanisms, which are at the core of breast cancer biology, is of critical importance. Such mechanisms may explain response to treatment, reveal novel targets or drive detection assays. To uncover such novel mechanisms, we used survival analysis on gene expression datasets encompassing 1363 patients. By iterating over the compendia of genes, we screened for their significance as prognosis biomarkers and identified SUMO-specific protease 5 (SENP5) to significantly stratify patients into two survival groups across five unrelated tested datasets. According to these findings, low expression of SENP5 is associated with good prognosis among breast cancer patients. Following these findings, we analyzed SENP5 silencing and show it is followed by inhibition of anchorage-independence growth, proliferation, migration and invasion in breast cancer cell lines. We further show that these changes are conducted via regulation of TGFßRI levels. These data relate to recent reports about the SUMOylation of TGFßRI. Following TGFßRI changes in expression, we show that one of its target genes, MMP9, which plays a key role in degrading the extracellular matrix and contributes to TGFß-induced invasion, is dramatically down regulated upon SENP5 silencing. This is the first report represents SENP5-TGFß-MMP9 cascade and its mechanistic involvement in breast cancer.