Prognostic impact of TP53INP1 gene expression in estrogen receptor α-positive breast cancer patients

概要

Background: Breast cancer is a prevalent disease and a leading cause of cancer death in women. Over 70% of breast cancers express estrogen receptor α(ERα). In ERα-positive breast cancers, estradiol is a key regulator of cell proliferation and survival. Treatment options for ERα-positive breast cancer patients include endocrine therapies that inhibit ERα signaling, either by antagonizing ligand binding to ERα, downregulating ERα or suppressing estrogen production. However, endocrine therapies do not always work in these patients, despite the expression of ERα in their tumors. Thus, resistance to endocrine therapies remains a major challenge in the treatment of ERα-positive breast cancers. Tumor protein 53-induced nuclear protein 1 (TP53INP1) is a key stress protein with tumor suppressor function. Several studies have demonstrated TP53INP1 downregulation in many cancers. In this study, we investigated the correlations of TP53INP1 mRNA expression in breast cancer tissues with prognosis and the correlations of microRNAs that regulate TP53INP1 expression in breast cancer patients with long follow-up.

Methods:A total of 453 invasive breast cancer tissues were analyzed for TP53INP1 mRNA expression. We examined correlations of clinicopathological factors and expression levels of TP53INP1 mRNA in these samples. The expressions of miR-155, miR-569 and markers associated with tumor-initiating capacity were also analyzed. The median follow-up period was 9.0 years.

Results:We found positive correlations between low expression of TP53INP1 mRNA and shorter disease-free survival and overall survival in breast cancer patients (P=0.0002 andP<0.0001, respectively), as well as in estrogen receptor α(ERα)-positive patients receiving adjuvant endocrine therapy (P=0.01 andP=0.0008, respectively). No correlations were found in ERα-negative patients. Low TP53INP1 mRNA levels positively correlated with higher grade and ERα-negativity. Multivariate analysis indicated that TP53INP1 mRNA level was an independent risk factor for overall survival both in overall breast cancer patients (hazard ratio, 2.13; 95% confidence interval, 1.17– 3.92) and ERα-positive patients (hazard ratio, 2.34; 95% confidence interval, 1.18–4.64).

Conclusions:We show that low expression of TP53INP1 is an independent factor of poor prognosis in breast cancer patients, especially ERα-positive patients.TP53INP1 might be a promising candidate biomarker and therapeutic target in ERα-positive breast cancer patients.