Abstract
Breast cancer is the most common type of cancer worldwide. However, the well-known molecular biomarkers are not enough to meet the needs of precision medicine. In search for novel targets in this regard, we reported ITSN1 (intersectin1) as one of the candidates through mRNA microarray analysis. In the present study, we reported that endocytic protein ITSN1-S exists not only in the cytoplasm but also in nuclei of breast cancer cells. ITSN1-S′ functional nuclear localization signal is within its residues 306–312. Its nuclear export signal (NES) resides within its SH3 domains. We also found, the interaction between the CC domain of nuclear ITSN1-S and the NT domain of nuclear DNA helicase II (NDH II) directly suppressed the DNA replication and nascent DNA synthesis by inhibiting the R-loops resolution in breast cancer cells. Furthermore, the interaction between the EH domains of cytoplasmic ITSN1-S and PI3KC2α inhibit cell migration and invasion by inactivating the PI3KC2α-AKT pathway. Our results were confirmed in both ITSN1 gene knockout cells and in vivo assays. Finally, our clinical data showed a potential application of the combined consideration of the cytoplasmic and nuclear ITSN1-S as an independent prognosis factor. In conclusion, our study revealed ITSN1-S′ novel positioning in the nuclei of breast cancer cells, its function in suppressing DNA replication, and its potential application in improved breast cancer prognosis.
Highlights
The incidence and mortality of breast cancer continue to increase and has become the most commonly diagnosed cancer worldwide in 2020 [1, 2]
Our present study focused on the role of ITSN1-S in breast cancer and our bioinformatics analysis from an online database showed that ITSN1 expression was downregulated in breast cancer tissues and its expression was positively associated with patient’s survival, suggesting ITSN1 may play a suppressive role in tumorigenesis of breast cancer
ITSN1-S could interact with nuclear DNA helicase II (NDH II) and co-localize in the nucleus In order to further investigate the role of nuclear ITSN1-S in proliferation and DNA replication, we examined whether ITSN1-S suppression affected the synthesis of new (“nascent”) DNA [16]
Summary
The incidence and mortality of breast cancer continue to increase and has become the most commonly diagnosed cancer worldwide in 2020 [1, 2]. Novel targets for improved prognosis are urgently needed. In this regard, we identified ITSN1 (intersectin1) as one of the candidates through the mRNA microarray analyses on the invasive ductal carcinoma (IDC) tissues with the paired adjacent tissues from 22 patients and 34 patients, respectively. Our previous studies showed that ITSN1-S promoted tumor development in malignant glioma [5, 9]. Our present study focused on the role of ITSN1-S in breast cancer and our bioinformatics analysis from an online database showed that ITSN1 expression was downregulated in breast cancer tissues and its expression was positively associated with patient’s survival, suggesting ITSN1 may play a suppressive role in tumorigenesis of breast cancer
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