ABSTRACT
Despite the current standard of care, breast cancer remains one of the leading causes of mortality in women worldwide, thus emphasizing the need for better predictive and therapeutic targets. ABI1 is associated with poor survival and an aggressive breast cancer phenotype, although its role in tumorigenesis, metastasis, and the disease outcome remains to be elucidated. Here, we define the ABI1-based seven-gene prognostic signature that predicts survival of metastatic breast cancer patients; ABI1 is an essential component of the signature. Genetic disruption of Abi1 in primary breast cancer tumors of PyMT mice led to significant reduction of the number and size of lung metastases in a gene dose-dependent manner. The disruption of Abi1 resulted in deregulation of the WAVE complex at the mRNA and protein levels in mouse tumors. In conclusion, ABI1 is a prognostic metastatic biomarker in breast cancer. We demonstrate, for the first time, that lung metastasis is associated with an Abi1 gene dose and specific gene expression aberrations in primary breast cancer tumors. These results indicate that targeting ABI1 may provide a therapeutic advantage in breast cancer patients.
Subject(s)
Adaptor Proteins, Signal Transducing , Breast Neoplasms , Cytoskeletal Proteins , Lung Neoplasms , Adaptor Proteins, Signal Transducing/genetics , Animals , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Carcinogenesis/genetics , Cell Line, Tumor , Cytoskeletal Proteins/genetics , Female , Gene Expression Regulation, Neoplastic , Humans , Lung Neoplasms/genetics , Lung Neoplasms/secondary , Mice , Neoplasm MetastasisABSTRACT
Our understanding of the molecular functions of the nucleocytoplasmic FMRP protein, which, if absent or dysfunctional, causes the fragile X syndrome (FXS), largely revolves around its involvement in protein translation regulation in the cytoplasm. Recent studies have begun honing in on the nuclear and genomic functions of FMRP. We have shown that during DNA replication stress, cells derived from FXS patients sustain increased level of R-loop formation and DNA double strand breaks. Here, we describe a transcriptomic analysis of these cells in order to identify those genes most impacted by the loss of FMRP with and without replication stress. We show that FMRP loss causes transcriptomic changes previously reported in untreated conditions. Importantly, we also show that replication stress, in addition to causing excess of DSB, results in down-regulation of transcription in virtually all DNA repair pathways. This finding suggests that despite normal DNA damage response, FXS patient-derived cells experience R-loop-induced DNA breakage as well as impaired DNA repair functions, effectively a double jeopardy. We suggest that it is imperative to deepen the understanding of the nuclear functions, particularly a genome protective function, of FMRP, which will lead to discoveries of novel therapeutic interventions for the FXS.
