EGFR and HER2 signaling in breast cancer brain metastasis

Sirkisoon, Sherona; Carpenter, Richard L.; Rimkus, Tadas; Miller, Lance D.; Metheny-Barlow, Linda J.; Lo, Hui-Wen

doi:10.2741/765

Cited by 31 publications

(9 citation statements)

References 128 publications

(148 reference statements)

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“…The EGFR family is comprised of four structurally similar receptors including EGFR (ErbB1 or HER1), ErbB2 (HER2), ErbB3 (HER3) and ErbB4 (HER4) [83, 84]. They are type I trans-membrane kinase receptors, which upon ligand binding in the extracellular domain, undergo dimerization and subsequent trans-phosphorylation in the intracellular domain.…”

Section: Cellular and Molecular Mechanisms Underlying Alcohol-indumentioning

confidence: 99%

“…EGFR and ErbB2 receive particular attention in the context of breast cancer etiology and therapy because of their frequent overexpression and hyperactivation in breast carcinomas [83]. Overexpression of EGFR and ErbB2 is associated with malignant breast cancers, increased metastasis, and poor prognosis [84–88]. …”

Section: Cellular and Molecular Mechanisms Underlying Alcohol-indumentioning

confidence: 99%

“…EGFR is activated by a number of ligands including EGF, amphiregulin, transforming growth factor alpha (TGFα), neuregulin 2β, betacellulin, heparin-binding EGF-like growth factor, and epiregulin [84, 89]. So far there is no identified ligand for ErbB2; the activation of ErbB2 is mediated through heterodimeric partners, e.g., EGFR, ErbB3 ErbB4 [85].…”

Section: Cellular and Molecular Mechanisms Underlying Alcohol-indumentioning

confidence: 99%

“…So far there is no identified ligand for ErbB2; the activation of ErbB2 is mediated through heterodimeric partners, e.g., EGFR, ErbB3 ErbB4 [85]. Upon activation, EGFR and ErbB2 trigger several important signaling cascades that play a key role in the carcinogenesis and aggressiveness of breast cancer, such as MAPK, PI3K/AKT/mTOR, Src, JAK/STAT3, PLC-γ/PKC and GSK3β/β-catenin [84, 88, 90–93]. The activation of these signaling cascades frequently promotes the proliferation, migration/invasion, growth, and metastasis of breast cancer [84].…”

Section: Cellular and Molecular Mechanisms Underlying Alcohol-indumentioning

confidence: 99%

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Cellular and molecular mechanisms underlying alcohol-induced aggressiveness of breast cancer

Wang

Zhang

et al. 2017

Pharmacological Research

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Breast cancer is a leading cause of morbidity and mortality in women. Both Epidemiological and experimental studies indicate a positive correlation between alcohol consumption and the risk of breast cancer. While alcohol exposure may promote the carcinogenesis or onset of breast cancer, it may as well enhance the progression and aggressiveness of existing mammary tumors. Recent progress in this line of research suggests that alcohol exposure is associated with invasive breast cancer and promotes the growth and metastasis of mammary tumors. There are multiple potential mechanisms involved in alcohol-stimulated progression and aggressiveness of breast cancer. Alcohol may increase the mobility of cancer cells by inducing cytoskeleton reorganization and enhancing the cancer cell invasion by causing degradation and reconstruction of the extracellular matrix (ECM). Moreover, alcohol may promote the epithelial-mesenchymal transition (EMT), a hallmark of malignancy, and impair endothelial integrity, thereby increasing the dissemination of breast cancer cells and facilitating metastasis. Furthermore, alcohol may stimulate tumor angiogenesis through the activation of cytokines and chemokines which promotes tumor growth. Additionally, alcohol may increase the cancer stem cell population which affects neoplastic cell behavior, aggressiveness, and the therapeutic response. Alcohol can be metabolized in the mammary tissues and breast cancer cells which produces reactive oxygen species (ROS), causing oxidative stress. Recent studies suggest that the epidermal growth factor receptor (EGFR) family, particularly ErbB2 (a member of this family), is involved in alcohol-mediated tumor promotion. Breast cancer cells or mammary epithelial cells over-expressing ErbB2 are more sensitive to alcohol’s tumor promoting effects. There is considerable cross-talk between oxidative stress and EGFR/ErbB2 signaling. This review further discusses how the interaction between oxidative stress and EGFR/ErbB2 signaling contributes to the cellular and molecular events associated with breast cancer aggressiveness. We also discuss the potential therapeutic approaches for cancer patients who drink alcoholic beverages.

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Section: Cellular and Molecular Mechanisms Underlying Alcohol-indumentioning

confidence: 99%

Section: Cellular and Molecular Mechanisms Underlying Alcohol-indumentioning

confidence: 99%

Section: Cellular and Molecular Mechanisms Underlying Alcohol-indumentioning

confidence: 99%

Section: Cellular and Molecular Mechanisms Underlying Alcohol-indumentioning

confidence: 99%

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Cellular and molecular mechanisms underlying alcohol-induced aggressiveness of breast cancer

Wang

Zhang

et al. 2017

Pharmacological Research

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“…We and others have shown the important role of EGFR and HER2 signaling in breast cancer brain metastasis (BCBM) formation [12, 13]. Alterations in both epidermal growth factor receptor (EGFR) and/or phosphatase and tensin homologue (PTEN) are associated with the triple-negative subtype [12, 14].…”

Section: Introductionmentioning

confidence: 99%

PTEN mediates the cross talk between breast and glial cells in brain metastases leading to rapid disease progression

et al. 2016

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Despite improvement of therapeutic treatments for breast cancer, the development of brain metastases has become a major limitation to life expectancy for many patients. Brain metastases show very commonly alterations in EGFR and HER2 driven pathways, of which PTEN is an important regulator. Here, we analyzed PTEN expression in 111 tissue samples of breast cancer brain metastases (BCBM). Loss of PTEN was found in a substantial proportion of BCBM samples (48.6%) and was significantly associated with triple-negative breast cancer (67.5%, p = 0.001) and a shorter survival time after surgical resection of brain metastases (p = 0.048). Overexpression of PTEN in brain-seeking MDA-MB-231 BR cells in vitro reduced activation of the AKT pathway, notably by suppression of Akt1 kinase activity. Furthermore, the migration of MDA-MB-231 BR cells in vitro was promoted by co-culturing with both astrocytes and microglial cells. Interestingly, when PTEN was overexpressed the migration was significantly inhibited. Moreover, in an ex vivo organotypic brain slice model, PTEN overexpression reduced invasion of tumor cells. This was accompanied by reduced astrocyte activation that was mediated by autocrine and paracrine activation of GM-CSF/ CSF2RA and AKT/ PTEN pathways. In conclusion, loss of PTEN is frequently detected in triple-negative BCBM patients and associated with poor prognosis. The findings of our functional studies suggest that PTEN loss promotes a feedback loop between tumor cells and glial cells, which might contribute to disease progression.

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HER2‐positive breast cancer brain metastasis: A new and exciting landscape

Zimmer

Swearingen²,

Anders³

2020

Cancer Reports

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Background: Brain metastases (BrM) incidence is 25% to 50% in women with advanced human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Radiation and surgery are currently the main local treatment approaches for central nervous system (CNS) metastases. Systemic anti-HER2 therapy following a diagnosis of BrM improves outcomes. Previous preclinical data has helped elucidate HER2 brain trophism, the blood-brain/blood-tumor barrier(s), and the brain tumor microenvironment, all of which can lead to development of novel therapeutic options. Recent findings: Several anti-HER2 agents are currently available and reviewed here, some of which have recently shown promising effects in BrM patients, specifically. New strategies driven by and focusing on brain metastasis-specific genomics, immunotherapy, and preventive strategies have shown promising results and are under development. Conclusions: The field of HER2+ breast cancer, particularly for BrM, continues to evolve as new therapeutic strategies show promising results in recent clinical trials. Increasing inclusion of patients with BrM in clinical studies, and a focus on assessing their outcomes both intracranially and extracranially, is changing the landscape for patients with HER2+ CNS metastases by demonstrating the ability of newer agents to improve outcomes.

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EGFR and HER2 signaling in breast cancer brain metastasis

Cited by 31 publications

References 128 publications

Cellular and molecular mechanisms underlying alcohol-induced aggressiveness of breast cancer

Cellular and molecular mechanisms underlying alcohol-induced aggressiveness of breast cancer

PTEN mediates the cross talk between breast and glial cells in brain metastases leading to rapid disease progression

HER2‐positive breast cancer brain metastasis: A new and exciting landscape

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