ErbB2 requires integrin α5 for anoikis resistance via Src regulation of receptor activity in human mammary epithelial cells

Haenssen, Keneshia K.; Caldwell, Sarah A.; Shahriari, Kristina; Jackson, Susan; Whelan, Kelly A.; Klein‐Szanto, Andres J.; Reginato, Mauricio J.

doi:10.1242/jcs.050906

Cited by 92 publications

(103 citation statements)

References 49 publications

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“…The figures including data using siRNAs show representative experiments from three or more independent experiments. Spry2 short hairpin RNAs (shRNAs) TRCN0000007522 and TRCN0000007524 were obtained from the RNAi Consortium, and lentiviruses were generated according to standard protocol (11).…”

Section: Methodsmentioning

confidence: 99%

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ErbB2 Stabilizes Epidermal Growth Factor Receptor (EGFR) Expression via Erk and Sprouty2 in Extracellular Matrix-detached Cells

Grassian

Schafer

Brugge

2011

Journal of Biological Chemistry

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Epithelial cells are dependent on extracellular matrix (ECM) attachment for maintenance of metabolic activity and suppression of apoptosis. Here we show that loss of ECM attachment causes down-regulation of epidermal growth factor receptor (EGFR) and ␤1 integrin protein and mRNA expression and that ErbB2, which is amplified in 25% of breast tumors, reverses these effects of ECM deprivation. ErbB2 rescue of ␤1 integrin mRNA and protein in suspended cells is dependent on EGFR, however, the rescue of EGFR expression does not require ␤1 integrin. We show that there is a significant decrease in the stability of EGFR in ECM-detached cells that is reversed by ErbB2 overexpression. Rescue of both EGFR and ␤1 integrin protein by ErbB2 is dependent on Erk activity and induction of its downstream target Sprouty2, a protein known to regulate EGFR protein stability. Interestingly, expression of EGFR and ␤1 integrin protein is more dependent on Erk/ Sprouty2 in ECM-detached ErbB2-overexpressing cells when compared with ECM-attached cells. These results provide further insight into the ErbB2-driven anchorage independence of tumor cells and provide a new mechanism for regulation of EGFR and ␤1 integrin expression in ECM-detached cells.One of the hallmarks of tumor cells is the ability to survive without attachment to the extracellular matrix (ECM) 3 (1). Detachment of normal epithelial cells from ECM leads to metabolic impairment and induction of apoptotic death (anoikis) (2-5). However, tumor cells are generally able to survive without ECM attachment, a property known as "anchorage independence" (2, 3). This is believed to allow tumor cells to invade and proliferate outside their natural ECM niches. For example, one early feature of breast cancer is the proliferation of cells into the ECM-deficient hollow lumen of the glandular epithelium (6). These premalignant cells are able to survive despite the lack of contact to the basement membrane. Additionally, it is believed that anchorage independence is an important aspect of the metastatic process, both for survival in the vasculature and lymphatic system and also for survival in distant sites with altered matrix environments (2). Thus, elucidation of the mechanisms responsible for tumor cell anchorage independence is critical for understanding of the tumorigenic processes and may lead to identification of novel drug targets.ECM detachment of mammary epithelial cells results in a decrease of growth factor signaling through the Mek/Erk and PI3K/Akt pathways (2, 4, 5, 7). This leads to decreased cell viability, both through the induction of anoikis and through a caspase-independent metabolic impairment (2, 4). We have previously found that decreased Erk activation in ECM-detached cells leads to increased expression of the pro-apoptotic protein, Bim (7-9). In addition, the lack of Akt signaling in the ECM-detached cells results in a dramatic decrease in glucose uptake and ATP levels, causing a severe energy deficiency (4). Therefore, survival of mammary epithelial cells under ECM-de...

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Section: Methodsmentioning

confidence: 99%

“…Overexpression of ErbB2, an ErbB family member that is amplified and overexpressed in breast tumors (10), maintains EGFR expression and EGF-induced signaling and permits cell survival under ECM-detached conditions (4,7,10,11). Several mechanisms contributing to ErbB2 regulation of survival and metabolism have been elucidated (4,7,10,(12)(13)(14).…”

mentioning

confidence: 99%

ErbB2 Stabilizes Epidermal Growth Factor Receptor (EGFR) Expression via Erk and Sprouty2 in Extracellular Matrix-detached Cells

Grassian

Schafer

Brugge

2011

Journal of Biological Chemistry

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“…[18][19][20] Interestingly, previous studies have shown that ErbB2 and EGFR, which are hyperactivated in a substantial percentage of IBC patients, 21 can effectively antagonize the anoikis program to facilitate anchorage-independent growth. [22][23][24][25][26][27][28] However, a detailed examination of the molecular mechanisms underlying anoikis inhibition in IBC cells has yet to be completed. In this study, we demonstrate that signaling from EGFR and ErbB2 through ERK/MAPK has a major role in the ability of IBC cells to survive in the absence of ECM attachment.…”

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confidence: 99%

Anoikis evasion in inflammatory breast cancer cells is mediated by Bim-EL sequestration

et al. 2014

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Inflammatory breast cancer (IBC) is a rare and highly invasive type of breast cancer, and patients diagnosed with IBC often face a very poor prognosis. IBC is characterized by the lack of primary tumor formation and the rapid accumulation of cancerous epithelial cells in the dermal lymphatic vessels. Given that normal epithelial cells require attachment to the extracellular matrix (ECM) for survival, a comprehensive examination of the molecular mechanisms underlying IBC cell survival in the lymphatic vessels is of paramount importance to our understanding of IBC pathogenesis. Here we demonstrate that, in contrast to normal mammary epithelial cells, IBC cells evade ECM-detachment-induced apoptosis (anoikis). ErbB2 and EGFR knockdown in KPL-4 and SUM149 cells, respectively, causes decreased colony growth in soft agar and increased caspase activation following ECM detachment. ERK/MAPK signaling was found to operate downstream of ErbB2 and EGFR to protect cells from anoikis by facilitating the formation of a protein complex containing Bim-EL, LC8, and Beclin-1. This complex forms as a result of Bim-EL phosphorylation on serine 59, and thus Bim-EL cannot localize to the mitochondria and cause anoikis. These results reveal a novel mechanism that could be targeted with innovative therapeutics to induce anoikis in IBC cells.

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“…To investigate the impact of cell transformation on the regulation of FLIP L expression and TRAIL sensitivity by EGF, we generated MCF10A cells that expressed a constitutively active form of the oncogene ERBB2/HER-2/neu. 33 In cells overexpressing the ERBB2 (NeuT) protein, the ERK1/2 pathway was not inhibited upon EGF withdrawal (Figure 7a …”

Section: Resultsmentioning

confidence: 99%

Control of FLIPL expression and TRAIL resistance by the extracellular signal-regulated kinase1/2 pathway in breast epithelial cells

et al. 2012

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Increased activation of the epidermal growth factor receptor (EGFR) is frequently observed in tumors, and inhibition of the signaling pathways originated in the EGFR normally renders tumor cells more sensitive to apoptotic stimuli. However, we show that inhibition of EGFR signaling in non-transformed breast epithelial cells by EGF deprivation or gefitinib, an inhibitor of EGFR tyrosine kinase, causes the upregulation of the long isoform of caspase-8 inhibitor FLICE-inhibitory protein (FLIP L ) and makes these cells more resistant to the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). We demonstrate that the extracellular signal-regulated kinase (ERK)1/2 pathway plays a pivotal role in the regulation of FLIP L levels and sensitivity to TRAIL-induced apoptosis by EGF. Upregulation of FLIP L upon EGF deprivation correlates with a decrease in c-Myc levels and c-Myc knockdown by siRNA induces FLIP L expression. FLIP L upregulation and resistance to TRAIL in EGF-deprived cells are reversed following activation of an estrogen activatable form of c-Myc (c-Myc-ER). Finally, constitutive activation of the ERK1/2 pathway in HER2/ERBB2-transformed cells prevents EGF deprivation-induced FLIP L upregulation and TRAIL resistance. Collectively, our results suggest that a regulated ERK1/2 pathway is crucial to control FLIP L levels and sensitivity to TRAIL in non-transformed cells, and this mechanism may explain the increased sensitivity of tumor cells to TRAIL, in which the ERK1/2 pathway is frequently deregulated.

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ErbB2 requires integrin α5 for anoikis resistance via Src regulation of receptor activity in human mammary epithelial cells

Cited by 92 publications

References 49 publications

ErbB2 Stabilizes Epidermal Growth Factor Receptor (EGFR) Expression via Erk and Sprouty2 in Extracellular Matrix-detached Cells

ErbB2 Stabilizes Epidermal Growth Factor Receptor (EGFR) Expression via Erk and Sprouty2 in Extracellular Matrix-detached Cells

Anoikis evasion in inflammatory breast cancer cells is mediated by Bim-EL sequestration

Control of FLIPL expression and TRAIL resistance by the extracellular signal-regulated kinase1/2 pathway in breast epithelial cells

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