ABSTRACT
BACKGROUND: 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 and P < 0.0001, respectively), as well as in estrogen receptor α (ERα)-positive patients receiving adjuvant endocrine therapy (P = 0.01 and P = 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.
Subject(s)
Biomarkers, Tumor/analysis , Breast Neoplasms/pathology , Carrier Proteins/biosynthesis , Heat-Shock Proteins/biosynthesis , Adult , Aged , Aged, 80 and over , Breast Neoplasms/mortality , Disease-Free Survival , Estrogen Receptor alpha/analysis , Female , Gene Expression Regulation, Neoplastic/physiology , Humans , MicroRNAs/metabolism , Middle Aged , PrognosisABSTRACT
BACKGROUND: Human epidermal growth factor receptor 2 (HER2) gene amplification/overexpression is a major therapeutic target in breast cancer, and has been introduced as a predictive biomarker to identify patients who may benefit from therapy with anti-HER2 agents. HER2 somatic mutations have been reported, and these may influence the effect of HER2-targeted drugs. METHODS: Here, we sought HER2 mutations in a group of 135 Japanese breast cancer patients with HER2-positive tumors. We analyzed HER2 mutations by direct Sanger sequencing of two major areas, the extracellular domain at position 309-310 and the kinase domain between 755 and 781. RESULTS: Two patients with the HER2 somatic mutation S310F in the extracellular domain were found in this series. One patient with the S310F mutation had a node-negative invasive ductal carcinoma classified as HER2 2+ by the HercepTest and fluorescence in situ hybridization (FISH) positive, and which was estrogen receptor (ER)-negative and progesterone receptor (PgR)-negative. Another patient with the S310F mutation had an apocrine carcinoma with seven lymph nodes positive for metastasis, classified as HER2 3+ by the HercepTest, but which was FISH-negative, as well as ER-negative and PgR-negative. Both patients had received adjuvant single-agent trastuzumab therapy, and had no local recurrence or distant metastasis for five and three years after surgery, respectively. CONCLUSIONS: Our data show that HER2 mutations are rare in HER2-positive Japanese breast cancer patients. The two mutations found in this study were identical, S310F. We suggest that in vitro experiments to determine whether the S310F mutation could be involved in resistance to anti-HER2 drugs are worthwhile in future.
Subject(s)
Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Mutation , Receptor, ErbB-2/genetics , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/therapeutic use , Asian People/genetics , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Breast Neoplasms/pathology , Female , Humans , Middle Aged , Receptor, ErbB-2/antagonists & inhibitors , Receptor, ErbB-2/metabolism , Trastuzumab/therapeutic use , Treatment OutcomeABSTRACT
BACKGROUND: Tamoxifen can reduce the occurrence of breast cancer by a half in high-risk women. Recently, a genome-wide association study identified two single-nucleotide polymorphisms (SNPs) near or in the CTSO and ZNF423 genes that were associated with breast cancer risk during tamoxifen therapy. We hypothesized that these two SNPs could be associated with increased recurrence in breast cancer patients who received adjuvant tamoxifen therapy. METHODS: A total of 586 breast carcinomas were available for SNP genotyping assays. TaqMan pre-designed SNP genotyping assays were used to identify the presence of CTSO rs10030044 and ZNF423 rs8060157. We then investigated the relationship between CTSO rs10030044 genotypes and mRNA expression levels of CTSO and BRCA1 in 290 breast cancer patients. RESULTS: We found a positive correlation between the variant GG genotype of CTSO rs10030044 and shorter disease-free survival, or overall survival in hormone receptor-positive breast cancer patients receiving adjuvant tamoxifen therapy. In contrast, this genotype was not associated with prognosis in hormone receptor-negative breast cancer patients. Multivariate Cox regression analysis revealed that this genotype was an independent factor indicating a poor prognosis in hormone receptor-positive breast cancer patients receiving adjuvant tamoxifen therapy. No association was found between CTSO genotype and mRNA expression of CTSO and BRCA1. ZNF423 rs8060157 genotype was not associated with prognosis in this study. CONCLUSION: We show that a SNP near the CTSO gene is a poor prognostic factor in breast cancer although further research might help to reveal the factors linking this genotype and prognosis.
