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

Abstract

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.

Keywords: Breast cancer; ITPR1; Immune infiltration; Prognosis; Prognostic biomarker.

Fig. 1

The expression of ITPR1 in distinct types of cancer diseases. A Expression of ITPR1 gene in 20 common tumors compared with paired normal tissues. Oncomine database was designed with fold change ≥ 2, P value ≤ 0.01 and gene rank ≥ top 10%. The graphic represents the numbers of datasets with statistically significant (p < 0.01) mRNA over-expression (red) or down-expression (blue) of ITPR11 (different types of cancer vs. corresponding normal tissue). B The Expression of ITPR1 in distinct types of cancer diseases (GEPIA). The differental methed choose Top 10 and use log2 (TPM + 1) for log-scale. C The Expression of ITPR1 in distinct types of cancer diseases (TIMER)

Fig. 2

Box plots of normal and tumor differentially expression of ITPR1 gene in different subtypes of breast cancer. A-F Box plots of normal and tumor differentially expression of ITPR1 gene in different subtypes of breast cancer. A Ductal breast carcinoma in situ stroma (B) Invasive ductal breast carcinoma stroma (C) Ductal breast carcinoma (D) Medullary breast carcinoma (E) Invasive breast carcinoma (F) Invasive ductal breast carcinoma.(ONCOMINE). G Box plots of normal and tumor expression of ITPR1 gene in Breast Cancer. (GEPIA). H ITPR1 gene expression with box plots in patients with breast cancer. (Bc-GenExMiner v4.3) (I) Representative immunohistochemistry images of distinct ITPR1 in Breast Cancer tissues and normal tissues (Human Protein Atlas)

Fig. 3

Bc-GenExMiner v4.3 to evaluate ITPR1 gene expression with box plots according to clinical parameters in patients with breast cancer. A SBR grade (B) NPI (C) nodal status (D) ER (E) PR (F) HER-2 (G) basal-like status (H) triple-negative status (I) basal-like and triple-negative status

Fig. 4

The prognostic value of mRNA level of ITPR1 in patients with breast cancer. A-I The survival curve of different datasets based on the expression of ITPR1 gene was used to analyze the prognostic value in breast cancer (PrognoScan). A Overall Survival (B) Distant Metastasis Free Survival (C) Distant Metastasis Free Survival (D) Distant Metastasis Free Survival (E) Relapse Free Survival (F) Relapse Free Survival (G) Disease Specific Survival (H) Overall Survival (I) Relapse Free Survival. J-L Prognostic value of mRNA expression of ITPR1 in patients with breast cancer (Kaplan–Meier Plotter). J Overall Survival (K) Relapse Free Survival (L) Distant Metastasis Free Survival

Fig. 5

ITPR1 expression is decreased in breast cancer and correlates with prognosis. A Representative immunohistochemistry (IHC) images of ITPR1 in Breast Cancer tissues and normal tissues. B Box plots of normal and cancer expression of ITPR1 gene in Breast tissues. C-D Prognostic value of expression of ITPR1 in patients with breast cancer (C) Overall Survival (D) Progression Free Survival. (Set ITPR1 score < 6 as low expression, ITPR1 score ≥ 6 as high expression) (E) ITPR1 was measured in different breast tissues by Western blot. F ITPR1 was measured in different breast cells by Western blot

Fig. 6

GO and KEGG enrichment analysis of ITPR1 and its 20 co-expression genes. (STRING). A PPI network. The nodes meant proteins; the edges meant the interaction of proteins (B) BP (C) CC (D) MF (E) KEGG

Fig. 7

Correlation of ITPR1 expression with immune infiltration level in Breast Cancer (TIMER). A BRCA (B) BRCA-Basal (C) BRCA-Luminal and (D) BRCA-Her2

Fig. 8

Co-expression analysis of gene ITPR1 and other genes. ( bc-GenExMiner software and Kaplan–Meier plotter). A, D, G, J The correlation between ITPR1 and co-expressed genes. B-C, E–F, H-I,K-L Survival analysis of ITPR1 and co-expressed genes