A Five-Gene Model Predicts Clinical Outcome in ER+/PR+, Early-Stage Breast Cancers Treated with Adjuvant Tamoxifen

Abstract

Primary breast carcinomas expressing both estrogen and progesterone receptors are most likely to respond to tamoxifen therapy, especially in patients with early-stage lesions. However, certain patients exhibit clinicopathologic features suggesting good prognosis relapse within 10 years, justifying a search for biomarkers identifying patients at risk for recurrence. Nine candidate genes associated with estrogen signaling were selected from microarray studies and combined with those for conventional biomarkers (ESR1, PGR, ERBB2). Expression of this 12-gene subset was analyzed by RT-qPCR in frozen tissue specimens from 60 early-stage, estrogen receptor (ER)+/progestin receptor (PR)+ breast cancers from patients treated with adjuvant tamoxifen. A multivariate model was created by Cox regression using a training data set and applied to an independent validation set. A five-gene model was developed from the training set (n = 36) that exhibited significant correlations with both relapse-free and overall survival. Applying this model to Kaplan-Meier regression, patients were separated into low-risk (100% relapse-free at 150 months) and high-risk (60% relapse-free at 150 months) groups (P = 0.03). When this model was applied to the validation set (n = 24), similar risk stratification was achieved for both relapse-free and overall survival (P = 0.01 and 0.04, respectively). We developed a five-gene model composed of PgR, BCL2, ERBB4 JM-a, RERG, and CD34 that identified early-stage, ER+/PR+ breast cancers in patients treated with tamoxifen that relapsed, although they exhibited clinicopathologic features suggesting good prognosis. Within this multivariate model, increased expression of PgR, ERBB4 JM-a, RERG, and CD34 was associated with increased survival, while increased expression of BCL2 was associated with decreased survival.

Artemin Stimulates Radio- and Chemo-resistance by Promoting TWIST1-BCL-2-dependent Cancer Stem Cell-like Behavior in Mammary Carcinoma Cells

“…Furthermore, BCL-2 is also associated with increased therapeutic resistance (57) and promotion of breast cancer-initiating cells (17). Significantly, in patients with ERϩ tumors treated with tamoxifen, increased BCL-2 expression was highly associated with a significantly worse survival outcome (58). Similarly, increased expression of ARTN has been reported to be associated with a worse survival outcome in such patients, an effect mediated by BCL-2 (4).…”

Protein Tyrosine Phosphatase 4A2 Expression Predicts Overall and Disease-Free Survival of Human Breast Cancer and Is Associated with Estrogen and Progestin Receptor Status

“…The utilization of laser capture microdissection allowed nondestructive removal of contaminating cell types that may influence downstream analyses. This extensive data set with the associated clinical follow-up provides a unique resource for identifying specific genes or gene combinations that may alter breast cancer progression and response [16,56,57]. Few previous studies suggested that PTP4A2 expression was correlated with tumor formation, migration, and invasion in cell lines and mouse models [33,48,54] and was elevated in primary breast tumors relative to normal breast tissues [48].…”

Expression of genes for peptide/protein hormones and their cognate receptors in breast carcinomas as biomarkers predicting risk of recurrence.

“…(Ma et al, 2003; Figure 2 describes the characteristics of the patient analyzed in the microarray Andres et al, 2013;Andres & Wittliff, 2011Kerr II & Wittliff, 2011). Relative gene expression levels were determined from qPCR with the ΔΔCt method using ACTB for normalization and Universal…”

“…(Fisher et al, 1987;Hammond et al, 2010;Kerr II & Wittliff, 2011) Since our goal is to decipher molecular signature for predicting breast cancer outcomes, we undertook the following analyses. Using gene expression levels from 118 ER+/PR+ breast cancer carcinomas, univariate Cox regression determined that the receptor SSTR2 exhibited significance for predicting OS (Table 8).…”

“…In Chapter IV, a meta-analysis was performed with public databases to compare our results with a few highly referenced databases. Andres, Brock, Andres, Edwards, & Wittliff, 2012;Andres & Wittliff, 2011Kerr II & Wittliff, 2011;Kidd et al, 2010;Kruer, Cummins, Powell, & Wittliff, 2013;Ma et al, 2003;Tecimer et al, 2000;J. Wittliff et al, 1998; J. L.…”