Expression of MALAT1 Promotes Trastuzumab Resistance in HER2 Overexpressing Breast Cancers

Abstract

Background: Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is associated with cancer progression. Our study examined the role of MALAT1 in breast cancer and the mechanisms involved in the regulation of MALAT1. Methods: In vitro cell and in vivo animal models were used to examine the role of MALAT1 in breast cancer. The interaction of FOXO1 (Forkhead Box O1) at the promoter region of MALAT1 was investigated by chromatin immunoprecipitation (ChIP) assay. Results: The data shows an elevated expression of MALAT1 in breast cancer tissues and cells compared to non-cancer tissues and cells. The highest level of MALAT1 was observed in metastatic triple-negative breast cancer and trastuzumab-resistant HER2 (human epidermal growth factor receptor 2) overexpressing (HER2+) cells. Knockdown of MALAT1 in trastuzumab-resistant HER2+ cells reversed epithelial to mesenchymal transition-like phenotype and cell invasiveness. It improved the sensitivity of the cell’s response to trastuzumab. Furthermore, activation of Akt by phosphorylation was associated with the upregulation of MALAT1. The transcription factor FOXO1 regulates the expression of MALAT1 via the PI3/Akt pathway. Conclusions: We show that MALAT1 contributes to HER2+ cell resistance to trastuzumab. Targeting the PI3/Akt pathway and stabilizing FOXO1 translocation could inhibit the upregulation of MALAT1.

Prognostic and immunological significance of metastasis associated lung adenocarcinoma transcript 1 among different kinds of cancers

“…Moreover, the high level of MALAT1 in breast cancer has been demonstrated and was related to tumor stage and size in other studies [41][42][43][44]. Oncogenic function of MALAT1 in breast cancer is correspondingly found [45][46][47], whereas Kim et al reported that MALAT1 suppressed breast cancer metastasis [48]. Several other studies also confirmed the inhibitory function of MALAT1 in breast cancer [49,50].…”

lncRNA MALAT1/miR‑26a/26b/ST8SIA4 axis mediates cell invasion and migration in breast cancer cell lines

“…Sun et al verified that MALAT1 regulated human umbilical vein endothelial cell (HUVEC) proliferation through sponging of miR-320a to regulate forkhead box protein (FOX)M1 expression ( 13 ). Upregulation of MALAT1 in breast cancer was revealed to induce epithelial-mesenchymal transition (EMT) and decrease trastuzumab sensitivity in human epidermal growth factor receptor (HER)2 + breast cancer ( 14 ). However, the role of MALAT1 in breast cancer development remains controversial, and an improved understanding of the functional relevance of MALAT1 to this disease is urgently needed.…”

Flubendazole Plays an Important Anti-Tumor Role in Different Types of Cancers

“…The main potential mechanism of anti-trastuzumab involves the interaction between HER2 and other family members, such as EGFR and HER3 [ 63 ]. The HER2 pathway is also involved in trastuzumab resistance [ 64 , 65 , 66 ]. The results of Yoon-Jae Kim et al showed that FLU promoted G2/M phase arrest and decreased cell viability in HER2-positive breast cancer cells in vitro.…”