Her2 activates NF-κB and induces invasion through the canonical pathway involving IKKα

Merkhofer, Evan; Cogswell, Patricia C.; Baldwin, Albert S.

doi:10.1038/onc.2009.410

Cited by 130 publications

(162 citation statements)

References 46 publications

(58 reference statements)

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“…Gene expression analysis of p65 knockdown cells led to a decrease in gene transcription levels of IL-6, IL-8, and TNF-a. (46) These data are consistent with our report as we observe the induction of all these cytokines and chemokines in addition to the accumulation of p65 in trastuzumabresistant cells. Moreover, our study also indicates that this induction of chemokine and cytokine levels is significantly sensitive to NF-kB inhibitor treatment, although there is marginal effect after lapatinib treatment.…”

Section: Mechanism Of Nf-jb Activation In Trastuzumab-resistant Cellssupporting

confidence: 82%

“…(50) IKKa is involved in both canonical and noncanonical pathways. (46,51,52) Our data indicate that the canonical pathways, involving both IKKa and IKKb, are important for the activation of NF-kB in trastuzumabresistant BT-474-R cells. Silencing and overexpression of both IKK kinases will determine the role of this kinase individually in the development of resistance in the BT-474-R cell line.…”

Section: Mechanism Of Nf-jb Activation In Trastuzumab-resistant Cellsmentioning

confidence: 94%

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Trastuzumab-Resistant Luminal B Breast Cancer Cells Show Basal-Like Cell Growth Features Through NF-κB-Activation

Kanzaki

Mukhopadhya

Cui

et al. 2016

Monoclonal Antibodies in Immunodiagnosis and Immunotherapy

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A major clinical problem in the treatment of breast cancer is mortality due to metastasis. Understanding the molecular mechanisms associated with metastasis should aid in designing new therapeutic approaches for breast cancer. Trastuzumab is the main therapeutic option for HER2+ breast cancer patients; however, the molecular basis for trastuzumab resistance (TZR) and subsequent metastasis is not known. Earlier, we found expression of basal-like molecular markers in TZR tissues from patients with invasive breast cancer. (1) The basal-like phenotype is a particularly aggressive form of breast cancer. This observation suggests that TZR might contribute to an aggressive phenotype. To understand if resistance to TZR can lead to basal-like phenotype, we generated a trastuzumab-resistant human breast cancer cell line (BT-474-R) that maintained human epidermal growth factor receptor 2 (HER2) overexpression and HER2 mediated signaling. Analysis showed that nuclear factor-kappa B (NF-kB) was constitutively activated in the BT-474-R cells, a feature similar to the basal-like tumor phenotype. Pharmacologic inhibition of NF-kB improved sensitivity of BT-474-R cells to trastuzumab. Interestingly, activation of HER2 independent NF-kB is not shown in luminal B breast cancer cells. Our study suggests that by activating the NF-kB pathway, luminal B cells may acquire a HER2+ basal-like phenotype in which NF-kB is constitutively activated; this notion is consistent with the recently proposed ''progression through grade'' or ''evolution of resistance'' hypothesis. Furthermore, we identified IKK-a/IKK-b and nuclear accumulation of RelA/p65 as the major determinants in the resistant cells. Thus our study additionally suggests that the nuclear accumulation of p65 may be a useful marker for identifying metastasis-initiating tumor cells and targeting RelA/p65 may limit metastasis of breast and other cancers associated with NF-kB activation.

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Section: Mechanism Of Nf-jb Activation In Trastuzumab-resistant Cellssupporting

confidence: 82%

Section: Mechanism Of Nf-jb Activation In Trastuzumab-resistant Cellsmentioning

confidence: 94%

Trastuzumab-Resistant Luminal B Breast Cancer Cells Show Basal-Like Cell Growth Features Through NF-κB-Activation

Kanzaki

Mukhopadhya

Cui

et al. 2016

Monoclonal Antibodies in Immunodiagnosis and Immunotherapy

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“…It has been previously suggested that HER2-induced NFkB activation is mediated by AKT activation (8). However, a later study showed that AKT is not required for the HER2-induced NF-kB activation (5). The same study further suggested that HER2 activates NF-kB through a canonical pathway that depends on IKKa, a component of IKK complex (5).…”

Section: Introductionmentioning

confidence: 79%

“…However, a later study showed that AKT is not required for the HER2-induced NF-kB activation (5). The same study further suggested that HER2 activates NF-kB through a canonical pathway that depends on IKKa, a component of IKK complex (5). However, the molecular link between HER2 and the IKK complex still remains to be determined.…”

Section: Introductionmentioning

confidence: 97%

“…It has been proposed that NF-kB plays a crucial role in the progression of many types of tumors, including HER2-positive breast cancer (4). For example, it has been shown that NF-kB is crucial for cell proliferation and invasion in HER2-positive breast cancer cells (5). In addition, the activation of NF-kB has been functionally linked to drug resistance in both HER2-positive and negative breast cancer cells (6,7).…”

Section: Introductionmentioning

confidence: 99%

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The CBM Complex Underwrites NF-κB Activation to Promote HER2-Associated Tumor Malignancy

Pan

Zhu

Zhou

et al. 2016

Molecular Cancer Research

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The HER2/Neu protein is overexpressed in a large fraction of human breast cancers. NF-kB is one of several transcription factors that are aberrantly activated in HER2-positive breast cancers; however, the molecular mechanism by which HER2 activates NF-kB remains unclear. The CARMA3-BCL10-MALT1 (CBM) complex is required for GPCR-and EGFR-induced NF-kB activation. In the current study, the role of the CBM complex in HER2-mediated NF-kB activation and HER2-positive breast cancer was investigated. Interestingly, HER2-mediated NF-kB activation requires protein kinase C (PKC) activity rather than AKT activity. Using biochemical and genetic approaches, it was shown that the CBM complex is required for HER2-induced NF-kB activation and functionally contributes to multiple properties of malignancy, such as proliferation, avoidance of apoptosis, migration, and invasion, both in vitro and in vivo. In addition, CARMA3-mediated NF-kB activity was required for the upregulation of two matrix metalloproteinases (MMP), MMP1 and MMP13, both of which contribute to tumor metastasis. To further access the physiologic role of CBM complex-mediated NF-kB activation in HER2-positive breast cancer progression, Malt1 knockout mice (Malt1 À/À ) were crossed with MMTV-Neu mice, in which mammary tumors spontaneously developed with HER2 overexpression. We observed delayed onset and prolonged progression time in mammary tumors in Malt1 knockout mice compared with control mice. In summary, these data demonstrate that the CBM complex is a crucial component mediating HER2-induced NF-kB signaling and tumor malignancy in HER2-positive breast cancer.Implications: The CBM complex bridges key signaling pathways to confer malignant phenotypes and metastatic potential in HER2-associated breast cancer.

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ErbB2 Activation Upregulates Glutaminase 1 Expression Which Promotes Breast Cancer Cell Proliferation

Qie

Chu

et al. 2014

J of Cellular Biochemistry

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Active glutamine utilization is critical for tumor cell proliferation. Glutaminolysis represents the first and rate-limiting step of glutamine utilization and is catalyzed by glutaminase (GLS). Activation of ErbB2 is one of the major causes of breast cancers, the second most common cause of death for women in many countries. However, it remains unclear whether ErbB2 signaling affects glutaminase expression in breast cancer cells. In this study, we show that MCF10A-NeuT cell line has higher GLS1 expression at both mRNA and protein levels than its parental line MCF10A, and knockdown of ErbB2 decreases GLS1 expression in MCF10A-NeuT cells. We further show that in these cells, ErbB2-mediated upregulation of GLS1 is not correlated to c-Myc expression. Moreover, activation of neither PI3K-Akt nor MAPK pathway is sufficient to upregulate GLS1 expression. Interestingly, inhibition of NF-κB blocks ErbB2-stimulated GLS1 expression, whereas stimulation of NF-κB is sufficient to enhance GLS1 levels in MCF10A cells, suggesting a PI3K-Akt-independent activation of NF-κB upregulates GLS1 in ErbB2-positive breast cancer cells. Finally, knockdown or inhibition of GLS1 significantly decreased the proliferation of breast cancer cells with high GLS1 levels. Taken together, our data indicate that ErbB2 activation promotes GLS1 expression via a PI3K-Akt-independent NF-κB pathway in breast cancer cells, identifying another oncogenic signaling pathway which stimulates GLS1 expression, and thus promoting glutamine utilization in cancer cells. These findings, if validated by in vivo model, may facilitate the identification of novel biochemical targets for cancer prevention and therapy.

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Her2 activates NF-κB and induces invasion through the canonical pathway involving IKKα

Cited by 130 publications

References 46 publications

Trastuzumab-Resistant Luminal B Breast Cancer Cells Show Basal-Like Cell Growth Features Through NF-κB-Activation

Trastuzumab-Resistant Luminal B Breast Cancer Cells Show Basal-Like Cell Growth Features Through NF-κB-Activation

The CBM Complex Underwrites NF-κB Activation to Promote HER2-Associated Tumor Malignancy

ErbB2 Activation Upregulates Glutaminase 1 Expression Which Promotes Breast Cancer Cell Proliferation

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