Systematic analysis of the expression and prognostic value of ITPR1 and correlation with tumor infiltrating immune cells in breast cancer.

BACKGROUND: ITPR1 is a key gene for autophagy, but its biological function is still unclear, and there are few studies on the correlation between ITPR1 gene expression and the occurrence and development of breast cancer. METHODS: Analyze the expression of ITPR1 through online databases such as Oncomine and TIMER. Kaplan-Meier plotter and other databases were used to evaluate the impact of ITPR1 on clinical prognosis. The expression of ITPR1 in analysis of 145 cases of breast cancer and 30 cases of adjacent normal tissue was detected by Immunohistochemistry. Statistical analysis was used to evaluate the clinical relevance and prognostic significance of abnormally expressed proteins. And the Western Blot was used to detect the expression of ITPR1 between breast cancer tissues and cells. The TIMER database studied the relationship between ITPR1 and cancer immune infiltration. And used the ROC plotter database to predict the response of ITPR1 to chemotherapy, endocrine therapy and anti-HER2 therapy in patients with breast cancer. RESULTS: Compared with normal breast samples, ITPR1 was significantly lower in patients with breast cancer. And the increased expression of ITPR1 mRNA was closely related to longer overall survival (OS), distant metastasis free survival (DMFS), disease specific survival (DSS) and relapse free survival (RFS) in breast cancer. And the expression level of ITPR1 was higher in patients treated with chemotherapy than untreated patients. In addition, the expression of ITPR1 was positively correlated with related gene markers of immune cells in different types of breast cancer, especially with BRCA basal tissue breast cancer. CONCLUSION: ITPR1 was lower expressed in breast cancer. The higher expression of ITPR1 suggested favorable prognosis for patients. ITPR1 was related to the level of immune infiltration, especially in BRCA-Basal patients. All research results indicated that ITPR1 might affect breast cancer prognosis and participate in immune regulation. In short, ITPR1 might be a potential target for breast cancer therapy.

CRM197 reverses paclitaxel resistance by inhibiting the NAC-1/Gadd45 pathway in paclitaxel-resistant ovarian cancer cells.

Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a new promising target for the treatment of ovarian cancer. Our previous study showed that cross-reacting material 197 (CRM197), a specific HB-EGF inhibitor, significantly reverses resistance against paclitaxel in paclitaxel-resistant ovarian cancer cells. However, the mechanism of the effect of CRM197 on the reversion of paclitaxel resistance was unclear. In this study, in vitro and in vivo data suggested that CRM197 treatment sensitized paclitaxel-resistant ovarian cancer cells to paclitaxel, at least in part, via nucleus accumbens-1 (NAC-1) and its downstream pathway, DNA damage-inducible 45-γ interacting protein (Gadd45gip1)/growth arrest and DNA damage-inducible 45 (Gadd45), in A2780/Taxol and SKOV3/Taxol cells. The results also showed that CRM197 activated the proapoptotic JNK/p38MAPK pathway to enhance caspase-3 activity and apoptosis by downregulation of the NAC-1/Gadd45gip1/Gadd45 pathway, leading to reversion of paclitaxel resistance in A2780/Taxol and SKOV3/Taxol cells. This study provides the first mechanism through which CRM197 significantly reverses resistance against paclitaxel by modulating the NAC-1/Gadd45gip1/Gadd45 pathway in paclitaxel-resistant ovarian cancer cells, and the mechanism of HB-EGF inhibition as a novel therapeutic strategy for patients with paclitaxel-resistant ovarian cancer.