Transcriptome-wide identification of mRNAs and lincRNAs associated with trastuzumab-resistance in HER2-positive breast cancer

Abstract

Approximately, 25–30% of early-stage breast tumors are classified at the molecular level as HER2-positive, which is an aggressive subtype of breast cancer. Amplification of the HER2 gene in these tumors results in a substantial increase in HER2 mRNA levels, and consequently, HER2 protein levels. HER2, a transmembrane receptor tyrosine kinase (RTK), is targeted therapeutically by a monoclonal antibody, trastuzumab (Tz), which has dramatically improved the prognosis of HER2-driven breast cancers. However, ~30% of patients develop resistance to trastuzumab and recur; and nearly all patients with advanced disease develop resistance over time and succumb to the disease. Mechanisms of trastuzumab resistance (TzR) are not well understood, although some studies suggest that growth factor signaling through other receptors may be responsible. However, these studies were based on cell culture models of the disease, and thus, it is not known which pathways are driving the resistance in vivo. Using an integrative transcriptomic approach of RNA isolated from trastuzumab-sensitive and trastuzumab-resistant HER2+ tumors, and isogenic cell culture models, we identified a small set of mRNAs and lincRNAs that are associated with trastuzumab-resistance (TzR). Functional analysis of a top candidate gene, S100P, demonstrated that inhibition of S100P results in reversing TzR. Mechanistically, S100P activates the RAS/MEK/MAPK pathway to compensate for HER2 inhibition by trastuzumab. Finally, we demonstrated that the upregulation of S100P appears to be driven by epigenomic changes at the enhancer level. Our current findings should pave the path toward new therapies for breast cancer patients.

ErbB2 signaling epigenetically suppresses microRNA‐205 transcription via Ras/Raf/MEK/ERK pathway in breast cancer

“…Merry et al . recently reported that S100P activates the Ras/Raf/MEK/ERK pathway to compensate for ErbB2 inhibition by trastuzumab . Based on these previous findings and our findings, miR‐205 reduction by ErbB2‐downstream Ras/Raf/MEK/ERK signaling might be responsible for trastuzumab resistance.…”

Long non‐coding RNAs differential expression in breast cancer subtypes: What do we know?

“…The same analysis in cell lines, resistant and sensitive to trastuzumab, showed 25 differentially expressed lincRNAs. Comparing the two results, seven were in common: linc‐NDUFV3‐1, linc‐FCGR1B‐7, linc‐NADSYN1‐1, linc‐LRRC49‐4, linc‐C6orf145‐3, linc‐GABRA5‐5, and linc‐VPS8‐3 …”

Whole Transcriptome Profiling: An RNA‐Seq Primer and Implications for Pharmacogenomics Research

“…Trastuzumab for patients with HER2‐positive breast cancer is an example of a number of existing drugs that have proved efficacy only for a group of patients with specific molecular features . Using RNA‐Seq for an integrative transcriptomic approach from trastuzumab‐sensitive and trastuzumab‐resistant HER2+ tumors, a small set of coding and noncoding (lincRNAs) associated with trastuzumab‐resistance, following validation with cancer cell lines . From functional investigation of top candidate genes, they demonstrated that inhibition of S100P results in reversing trastuzumab resistance .…”

“…84 Using RNA-Seq for an integrative transcriptomic approach from trastuzumab-sensitive and trastuzumab-resistant HER2+ tumors, a small set of coding and noncoding (lincRNAs) associated with trastuzumabresistance, following validation with cancer cell lines. 85 From functional investigation of top candidate genes, they demonstrated that inhibition of S100P results in reversing trastuzumab resistance. 85 Through an unbiased gene expression investigation with RNA-Seq, this study revealed clinically relevant mechanism of trastuzumab-resistance, and outlined potential targets for novel therapeutic strategies.…”

“…85 From functional investigation of top candidate genes, they demonstrated that inhibition of S100P results in reversing trastuzumab resistance. 85 Through an unbiased gene expression investigation with RNA-Seq, this study revealed clinically relevant mechanism of trastuzumab-resistance, and outlined potential targets for novel therapeutic strategies.…”