Apoptosis-, proliferation, immune function-, and drug resistance- related genes in ER positive, HER2 positive and triple negative breast cancer

Abstract

The aim of our study was to examine an association between gene expression assessed using a 23-gene microarray and receptor status of breast cancer samples categorized as ER positive, HER2 positive and triple negative subtypes. The ER positive cohort was subsequently divided into Luminal A, Luminal B HER2 negative and Luminal B HER2 positive subtypes. Core-needle biopsies were collected from 78 female patients with inoperable locally advanced breast cancer or resectable tumors suitable for downstaging, before any treatment. Expressions of 23 genes were determined by means of TagMan Low Density Arrays. Analysis of variance was used to select genes with discriminatory potential between receptor subtypes. We introduced a correction for false discovery rates (presented as q values) due to testing multiple hypothesis. Pairwise post-hoc comparisons of receptor subtypes were performed using Tukey 's HSD test. Five genes out of a 23-gene microarray differed significantly in relation to breast cancer receptor-based subtypes. Among these five genes, we identified: BCL2 (p=0.0002, q=0.0009), MKI67 (p=0.0037, q=0.0064), IGF1R (p=0.0040, q=0.0064), FOXC1 (p=0.0113, q=0.0135) and IRF1 (p=0.0435, q=0.0416) as ones showing ER positive, HER2 positive and triple negative -subtype specific expression profiles. When incorporating Luminal A, Luminal B HER2 negative, Luminal B HER2 positive subtypes into analysis, four genes: BCL2 (p=0.0006, q=0.0034), MKI67 (p=0.0078, q=0.0198), FOXC1 (p=0.0102, q=0.0198) and IGF1R (p=0.0174, q=0.0254) were selected. Elevated levels of IGF1R and BCL2 were significantly linked with Luminal A subtype. Triple negative breast cancer subtype was associated with higher expression of IRF1, FOXC1 and MKI67. In HER2 positive cohort lower expression of all five analyzed genes was noted.

Role of IGF1R in Breast Cancer Subtypes, Stemness, and Lineage Differentiation

“…Estrogen receptor α is a major regulator of IGF signaling, due in part to transcriptional activation of IGF1R and many other IGF signaling components such as IRS1 ( 57 – 59 ). Consistent with this, the hormonally driven luminal subtypes tend to have higher levels of IGF1R and IRS expression as opposed to tumors that are less hormonally driven (triple negative and ERBB2 + ) ( 60 , 61 ). IGF1R is expressed in 52 and 84% of Luminal A and 57.5 and 76% of Luminal B tumors, respectively ( 62 , 63 ).…”

“…As discussed above, IGF1R expression is essential for driving luminal alveolar differentiation, linking IGF1R to the luminal lineage. In breast cancer, IGF1R expression correlates most strongly with luminal breast cancers ( 60 , 61 ). This expression may be a result of ER-driven growth through IGF1R rather than a causative link between IGF1R and the luminal lineage; nevertheless, the presence of IGF1R may still affect cell signaling and perhaps cell lineage.…”

Evaluation of the ability of adjuvant tamoxifen‐benefit gene signatures to predict outcome of hormone‐naive estrogen receptor‐positive breast cancer patients treated with tamoxifen in the advanced setting

“…The predictive power of the genes persisted despite different clinical settings (adjuvant vs. first-line treatment, menopausal status, and adjuvant chemotherapy), clinical sampling (countries, laboratories) and molecular assays (cDNA synthesis protocol, qPCR assays, and normalization procedures). This study provides support for the findings of several other studies (Albain et al, 2009;Hwang et al, 2012;Kerr and Wittliff, 2011;Kolacinska et al, 2012;Linke et al, 2006;Lyng et al, 2013;Mangerini et al, 2012;Nehra et al, 2010;Paik, 2007;Sgroi et al, 2013;Tozlu et al, 2006;Wang et al, 2009) indicating that BCL2 is a biomarker for endocrine response. The addition of BCL2 (and NAT1 and BCAR3) to standard biological measures might be considered for future hormone receptor-positive clinical studies.…”

Mutational profiles in triple-negative breast cancer defined by ultradeep multigene sequencing show high rates of PI3K pathway alterations and clinically relevant entity subgroup specific differences

“…The first group, luminal-like TNBC, is characterized by the lack of cytokeratin 5/6 and 14 as well as EGFR expression. We believe that this subtype represents de-differentiated luminal breast cancers, since BCL2 expression had been preserved in most cases, an anti-apoptotic protein frequently expressed in luminal A and luminal B breast cancer but generally not in HER2 positive or TNBC tumors [ 12 , 35 ]. This assumption is supported by our sequencing data showing a comparably low frequency of TP53 mutations in this tumor subgroup.…”