Abstract P2-07-06: Niclosamid overcomes epithelial-mesenchymal transition of lapatinib resistance through inhibiting Src activation in HER2 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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Association of epithelial-mesenchymal transition with lapatinib resistance through multipe pathways activation in HER2-positive breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.15_suppl.e11579 ◽

2014 ◽

Vol 32 (15_suppl) ◽

pp. e11579-e11579 ◽

Cited By ~ 2

Author(s):

Junjun Liu ◽

Xiaosong Chen ◽

Yan Mao ◽

Qing Qu ◽

Kunwei Shen

Keyword(s):

Breast Cancer ◽

Epithelial Mesenchymal Transition ◽

Her2 Positive ◽

Mesenchymal Transition ◽

Her2 Positive Breast Cancer ◽

Positive Breast Cancer

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Targeting Cancer Stem Cells and Metastasis with Epigenetic Modulation and Anti-HER2 Therapy: Phase I/II Trial of Vorinostat in Combination with Lapatinib

Clinical Oncology and Research ◽

10.31487/j.cor.2020.07.04 ◽

2020 ◽

pp. 1-12

Author(s):

Saranya Chumsri ◽

Amanda Schech ◽

Angela Brodie ◽

Jane Lewis ◽

Katherine Tkaczuk ◽

...

Keyword(s):

Breast Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Phase I ◽

Single Agent ◽

Preclinical Studies ◽

Her2 Positive ◽

Mesenchymal Transition ◽

Her2 Positive Breast Cancer ◽

Positive Breast Cancer

Purpose: Considerable preclinical and clinical data indicate that only a small subset of tumor cells has longterm proliferating capacity. These cells are termed cancer stem cells (CSCs). Failure to eradicate CSCs is hypothesized to be a cause of cancer recurrence after potentially curative therapies. Therefore, approaches that target CSCs have the potential to improve outcomes. We evaluated the combination of vorinostat and lapatinib to target CSCs and metastasis. Experimental Design: We conducted preclinical studies and a phase I/II clinical trial to determine the effects of vorinostat and lapatinib to CSCs. Results: Our preclinical studies demonstrated that vorinostat and lapatinib further reduced CSCs compared to either single agent. Reduction in self-renewal proteins, mammospheres, epithelial-mesenchymal transition (EMT) markers, and cell migration was also observed. Based on these findings, the combination was evaluated in the phase I trial to which a total of 12 patients were enrolled. Dose-limiting toxicity was not observed in phase I, and the recommended phase II dose was vorinostat 400 mg 4 days on 3 days off and lapatinib 1,250 mg daily. In HER2-positive breast cancer patients, the clinical benefit rate was observed in 43% of subjects. Interestingly, patients who remained on vorinostat and lapatinib did not develop any new site of metastasis. Conclusion: The combination of vorinostat and lapatinib is safe and active in HER2-positive breast cancer. Further studies are needed to evaluate this strategy to target CSCs and metastasis.

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

Life ◽

10.3390/life11090868 ◽

2021 ◽

Vol 11 (9) ◽

pp. 868

Author(s):

Babak Nami ◽

Avrin Ghanaeian ◽

Corbin Black ◽

Zhixiang Wang

Keyword(s):

Breast Cancer ◽

Tumor Cells ◽

Breast Cancer Cells ◽

Epithelial Mesenchymal Transition ◽

Epigenetic Silencing ◽

Her2 Expression ◽

Her2 Positive ◽

Mesenchymal Transition ◽

Erbb2 Gene ◽

Positive 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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