scholarly journals The Receptor Tyrosine Kinase AXL Is Required at Multiple Steps of the Metastatic Cascade During HER2-Positive Breast Cancer Progression

2018 ◽  
Author(s):  
Marie-Anne Goyette ◽  
Sttphanie Duhamel ◽  
LLo Aubert ◽  
Ariane Pelletier ◽  
Paul Savage ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tyrosine Kinase ◽  
Cancer Progression ◽  
Receptor Tyrosine Kinase ◽  
Breast Cancer Progression ◽  
Her2 Positive ◽  
Metastatic Cascade ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer

scholarly journals Targeting the EphB4 receptor tyrosine kinase sensitizes HER2-positive breast cancer cells to Lapatinib

2020 ◽  
Vol 475 ◽  
pp. 53-64 ◽  
Author(s):  
Jinlei Ding ◽  
Yating Yao ◽  
Gena Huang ◽  
Xiaonan Wang ◽  
Jingyan Yi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tyrosine Kinase ◽  
Cancer Cells ◽  
Receptor Tyrosine Kinase ◽  
Breast Cancer Cells ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer

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

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.

HER-targeted tyrosine kinase inhibitors enhance response to trastuzumab and pertuzumab in HER2-positive breast cancer

2018 ◽  
Vol 37 (3) ◽  
pp. 441-451 ◽  
Author(s):  
Alexandra Canonici ◽  
Laura Ivers ◽  
Neil T. Conlon ◽  
Kasper Pedersen ◽  
Nicola Gaynor ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer

Recent Updates on the Therapeutic Potential of HER2 Tyrosine Kinase Inhibitors for the Treatment of Breast Cancer

2018 ◽  
Vol 18 (4) ◽  
pp. 306-327 ◽  
Author(s):  
Heena Singla ◽  
Anjana Munshi ◽  
Raja Paramjit Singh Banipal ◽  
Vinod Kumar
Keyword(s):  
Breast Cancer ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Therapeutic Potential ◽  
Her2 Receptor ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Development Of Resistance ◽  
Positive Breast Cancer

HER2 positive breast cancer is characterized by the low survival rate in the metastatic patients. Development of resistance and disease-relapse are the major problems associated with the currently available therapies for HER2 positive breast cancer. There are two major targeted therapies for HER2 positive breast cancer viz. monoclonal antibodies and tyrosine-kinase inhibitors, and both of these therapies have their advantages and limitations. To address the limitations associated with the existing therapies, use of antibodies and TKIs as combination therapy proved to be more effective. Various chemical modifications can be performed on tyrosine-kinase inhibitors to develop novel ligands with increased selectivity for HER2 kinase. A number of tyrosine-kinase inhibitors are in various phases of clinical trials for the treatment of HER2 positive breast cancer. In the current review article, recent developments on various HER2 tyrosine-kinase inhibitors have been reported. Various structurally different scaffolds bind to the HER2 receptor and exhibit potent anti-cancer activities. The structural and pharmacophoric requirements of the scaffolds are discussed in detail so as to discover effective drug candidates for the treatment of HER2 positive breast cancer.

scholarly journals RNF40-dependent epigenetic regulation of actin cytoskeletal dynamics is required for HER2-driven mammary tumorigenesis

2020 ◽  
Author(s):  
Florian Wegwitz ◽  
Evangelos Prokakis ◽  
Anastasija Pejkovska ◽  
Robyn Laura Kosinsky ◽  
Markus Glatzel ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Transcriptional Activation ◽  
Breast Cancer Subtype ◽  
Human Tumor ◽  
Actin Dynamics ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer

AbstractThe HER2-driven breast cancer subtype displays a particularly aggressive behavior. Alterations of the epigenome are common in cancers and represent attractive novel molecular therapeutic targets. Monoubiquitination of histone 2B (H2Bub1) by its obligate heterodimeric E3 ubiquitin ligase complex RNF20/RNF40 has been described to have tumor suppressor functions and loss of H2Bub1 has been associated with cancer progression. In this study, we utilized human tumor samples, cell culture models, and a mammary carcinoma mouse model with tissue-specific Rnf40 deletion and identified an unexpected tumor-supportive role of RNF40 in HER2-positive breast cancer. We demonstrate that RNF40-driven H2B monoubiquitination is essential for transcriptional activation of RHO/ROCK/LIMK pathway components and proper actin cytoskeleton dynamics through a trans-histone crosstalk with histone 3 lysine 4 trimethylation (H3K4me3). Collectively, this work demonstrates a previously unknown essential role of RNF40 in HER2-positive breast cancer, revealing the RNF20/RNF40/H2Bub1 axis as a possible tumor context-dependent therapeutic target in breast cancer.Statement of significanceHER2-positive breast cancer patients frequently develop resistance to anti-HER2 therapies. Here we demonstrate that RNF20/RNF40-mediated H2B monoubiquitination supports the oncogenic properties of cancer cells of this subtype by regulating actin dynamics. The RNF20/RNF40/H2Bub1 axis may therefore represent an attractive drug target for novel therapies.

scholarly journals The Receptor Tyrosine Kinase TrkA Is Increased and Targetable in HER2-Positive Breast Cancer

Biomolecules ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 1329
Author(s):  
Nathan Griffin ◽  
Mark Marsland ◽  
Severine Roselli ◽  
Christopher Oldmeadow ◽  
John Attia ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tyrosine Kinase ◽  
Cell Lines ◽  
Kinase Inhibitor ◽  
Breast Cancer Cell Lines ◽  
Tyrosine Kinase Receptor ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Ductal Carcinomas ◽  
Positive Breast Cancer

The tyrosine kinase receptor A (NTRK1/TrkA) is increasingly regarded as a therapeutic target in oncology. In breast cancer, TrkA contributes to metastasis but the clinicopathological significance remains unclear. In this study, TrkA expression was assessed via immunohistochemistry of 158 invasive ductal carcinomas (IDC), 158 invasive lobular carcinomas (ILC) and 50 ductal carcinomas in situ (DCIS). TrkA was expressed in cancer epithelial and myoepithelial cells, with higher levels of TrkA positively associated with IDC (39% of cases) (p < 0.0001). Interestingly, TrkA was significantly increased in tumours expressing the human epidermal growth factor receptor-2 (HER2), with expression in 49% of HER2-positive compared to 25% of HER2-negative tumours (p = 0.0027). A panel of breast cancer cells were used to confirm TrkA protein expression, demonstrating higher levels of TrkA (total and phosphorylated) in HER2-positive cell lines. Functional investigations using four different HER2-positive breast cancer cell lines indicated that the Trk tyrosine kinase inhibitor GNF-5837 reduced cell viability, through decreased phospho-TrkA (Tyr490) and downstream AKT (Ser473) activation, but did not display synergy with Herceptin. Overall, these data highlight a relationship between the tyrosine kinase receptors TrkA and HER2 and suggest the potential of TrkA as a novel or adjunct target for HER2-positive breast tumours.

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