Epigenetic Silencing of HER2 Expression during Epithelial-Mesenchymal Transition Leads to Trastuzumab Resistance in Breast Cancer

HER2 receptor tyrosine kinase (encoded by the ERBB2 gene) is overexpressed in approximately 25% of all breast cancer tumors (HER2-positive breast cancers). Resistance to HER2-targeting therapies is partially due to the loss of HER2 expression in tumor cells during treatment. However, little is known about the exact mechanism of HER2 downregulation in HER2-positive tumor cells. Here, by analyzing publicly available genomic data we investigate the hypothesis that epithelial-mesenchymal transition (EMT) abrogates HER2 expression by epigenetic silencing of the ERBB2 gene as a mechanism of acquired resistance to HER2-targeted therapies. As result, HER2 expression was found to be positively and negatively correlated with the expression of epithelial and mesenchymal phenotype marker genes, respectively. The ERBB2 chromatin of HER2-high epithelial-like breast cancer cells and HER2-low mesenchymal-like cells were found to be open/active and closed/inactive, respectively. Decreased HER2 expression was correlated with increased EMT phenotype, inactivated chromatin and lower response to lapatinib. We also found that induction of EMT in the HER2-positive breast cancer cell line BT474 resulted in downregulated HER2 expression and reduced trastuzumab binding. Our results suggest that ERBB2 gene silencing by epigenetic regulation during EMT may be a mechanism of de novo resistance of HER2-positive breast cancer cells to trastuzumab and lapatinib.

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Epigenetic downregulation of HER2 during EMT leads to tumor resistance to HER2-targeted therapies in breast cancer

10.1101/2020.03.24.006379 ◽

2020 ◽

Author(s):

Babak Nami ◽

Avrin Ghanaeian ◽

Zhixiang Wang

Keyword(s):

Breast Cancer ◽

Tyrosine Kinase ◽

Gene Silencing ◽

Receptor Tyrosine Kinase ◽

Breast Cancer Cells ◽

Breast Cancers ◽

Her2 Expression ◽

Her2 Positive ◽

Her2 Positive Breast Cancer ◽

Positive Breast Cancer

ABSTRACTHER2 receptor tyrosine kinase (encoded by ERBB2 gene) is overexpressed in approximately 25% of all breast cancer tumors (known as HER2-positive breast cancers). Overexpression of HER2 causes overactivation of downstream receptor tyrosine kinase pathways including PI3K/Akt and MAPK pathways and is a poor prognosis factor in breast cancer. Tyrosine kinase inhibitor lapatinib and anti-HER2 monoclonal antibodies trastuzumab and pertuzumab are FDA-approved HER2-targeted drugs for treatment of HER2-positive breast cancers. However, development of de novo resistance to HER2 blockade occurs in majority of patients after treatment started. Resistance to HER2 targeting therapies partially due to the loss of HER2 expression on their tumor cells during the treatment. But little is known about the exact mechanism of loss of HER2 on originally HER2-positive tumor cells. Downregulation of extracellular HER2 by metalloproteinases during epithelial-mesenchymal transition (EMT) in trastuzumab-resistant/lapatinib-sensitive cells has been shown by limited studies, however, the mechanism of ERBB2 gene silencing during EMT and in the mesenchymal-like cells derived from trastuzumab-resistant/lapatinib-resistant HER2-positive breast tumors was entirely unknown. In this study, hypothesized that EMT abrogates HER2 expression by chromatin-based epigenetic silencing of ERBB2 gene as a mechanism of acquired resistance to HER2-targeted therapies. we found that HER2 expression is positively and negatively correlated with the expression of epithelial and mesenchymal phenotype marker genes respectively in breast cancer tumors. We also found that chromatin of ERBB2 gene in HER2-high epithelial-like breast cancer cells is active, while, the chromatin is inactive in HER2-low mesenchymal-like cells. HER2-low breast cancer cell line also revealed less promoter-enhancer interaction and small chromatin loops compared to the HER2-high cell lines. The lower HER2 expression, the higher EMT phenotype, and inactivated chromatin all were found correlated with a lower response to lapatinib. The higher EMT phenotype was found correlated with a lower response to lapatinib. We also found that induction of EMT of HER2-positive breast cancer BT474 cells results in downregulated HER2 expression and lower binding rate of trastuzumab to the cells. These results show that the downregulation of HER2 in mesenchymal-like cells in the culture of HER2-positive breast cancer cell lines was due to ERBB2 gene silencing by epigenetic reprogramming of the cells during EMT. These results indicate that ERBB2 gene silencing by epigenetic regulation during EMT is the main mechanism of resistance of HER2-positive breast cancer cells to trastuzumab and lapatinib.

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MiR-206 suppresses epithelial mesenchymal transition by targeting TGF-β signaling in estrogen receptor positive breast cancer cells

Oncotarget ◽

10.18632/oncotarget.8233 ◽

2016 ◽

Vol 7 (17) ◽

pp. 24537-24548 ◽

Cited By ~ 40

Author(s):

Kai Yin ◽

Wenjin Yin ◽

Yaohui Wang ◽

Liheng Zhou ◽

Yu Liu ◽

...

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Epithelial Mesenchymal Transition ◽

Mesenchymal Transition ◽

Estrogen Receptor Positive ◽

Positive Breast Cancer

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Glucocorticoids induce CCN5/WISP-2 expression and attenuate invasion in oestrogen receptor-negative human breast cancer cells

Biochemical Journal ◽

10.1042/bj20120311 ◽

2012 ◽

Vol 447 (1) ◽

pp. 71-79 ◽

Cited By ~ 16

Author(s):

Nathalie Ferrand ◽

Emilien Stragier ◽

Gérard Redeuilh ◽

Michèle Sabbah

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Oestrogen Receptor ◽

Breast Cancer Cells ◽

Epithelial Mesenchymal Transition ◽

Integration Site ◽

Tissue Growth ◽

Glucocorticoid Treatment ◽

Mesenchymal Transition ◽

Positive Breast Cancer

CCN5 (cysteine-rich 61/connective tissue growth factor/nephroblastoma overexpressed 5)/WISP-2 [WNT1 (wingless-type MMTV integration site family, member 1)-inducible signalling pathway protein 2] is an oestrogen-regulated member of the CCN family. CCN5 is a transcriptional repressor of genes associated with the EMT (epithelial–mesenchymal transition) and plays an important role in maintenance of the differentiated phenotype in ER (oestrogen receptor)-positive breast cancer cells. In contrast, CCN5 is undetectable in more aggressive ER-negative breast cancer cells. We now report that CCN5 is induced in ER-negative breast cancer cells such as MDA-MB-231 following glucocorticoid exposure, due to interaction of the endogenous glucocorticoid receptor with a functional glucocorticoid-response element in the CCN5 gene promoter. Glucocorticoid treatment of MDA-MB-231 cells is accompanied by morphological alterations, decreased invasiveness and attenuated expression of mesenchymal markers, including vimentin, cadherin 11 and ZEB1 (zinc finger E-box binding homeobox 1). Interestingly, glucocorticoid exposure did not increase CCN5 expression in ER-positive breast cancer cells, but rather down-regulated ER expression, thereby attenuating oestrogen pathway signalling. Taken together, our results indicate that glucocorticoid treatment of ER-negative breast cancer cells induces high levels of CCN5 expression and is accompanied by the appearance of a more differentiated and less invasive epithelial phenotype. These findings propose a novel therapeutic strategy for high-risk breast cancer patients.

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Elaeagnus angustifolia Plant Extract Inhibits Epithelial-Mesenchymal Transition and Induces Apoptosis via HER2 Inactivation and JNK Pathway in HER2-Positive Breast Cancer Cells

Molecules ◽

10.3390/molecules25184240 ◽

2020 ◽

Vol 25 (18) ◽

pp. 4240 ◽

Cited By ~ 1

Author(s):

Ayesha Jabeen ◽

Anju Sharma ◽

Ishita Gupta ◽

Hadeel Kheraldine ◽

Semir Vranic ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Cell Lines ◽

Cancer Cell ◽

Epithelial Mesenchymal Transition ◽

Elaeagnus Angustifolia ◽

Her2 Positive ◽

Mesenchymal Transition ◽

Her2 Positive Breast Cancer ◽

Positive Breast Cancer

Elaeagnus angustifolia (EA) is a medicinal plant used for treating several human diseases in the Middle East. Meanwhile, the outcome of EA extract on HER2-positive breast cancer remains nascent. Thus, we herein investigated the effects of the aqueous EA extract obtained from the flowers of EA on two HER2-positive breast cancer cell lines, SKBR3 and ZR75-1. Our data revealed that EA extract inhibits cell proliferation and deregulates cell-cycle progression of these two cancer cell lines. EA extract also prevents the progression of epithelial-mesenchymal transition (EMT), an important event for cancer invasion and metastasis; this is accompanied by upregulations of E-cadherin and β-catenin, in addition to downregulations of vimentin and fascin, which are major markers of EMT. Thus, EA extract causes a drastic decrease in cell invasion ability of SKBR3 and ZR75-1 cancer cells. Additionally, we found that EA extract inhibits colony formation of both cell lines in comparison with their matched control. The molecular pathway analysis of HER2 and JNK1/2/3 of EA extract exposed cells revealed that it can block HER2 and JNK1/2/3 activities, which could be the major molecular pathway behind these events. Our findings implicate that EA extract may possess chemo-preventive effects against HER2-positive breast cancer via HER2 inactivation and specifically JNK1/2/3 signaling pathways.

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