ErbB2-dependent downregulation of a pro-apoptotic protein Perp is required for oncogenic transformation of breast epithelial cells

Khan, Iman; Yoo, Byounghyun; Masson, Olivier; Baron, Sylvain; Corkery, Dale; Dellaire, Graham; Attardi, Laura D.; Rosen, Kirill V.

doi:10.1038/onc.2016.109

Cited by 20 publications

(40 citation statements)

References 57 publications

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“…Indeed, G1 cell cycle arrest due to p27 Kip1 suppression of CDK2 activity is a documented effect of trastuzumab treatment [ 41 ]. Blockade of HER2 can also limit expression of the anti-apoptotic Mcl-1 protein, and promote apoptosis [ 42 , 43 ]. These studies should be expanded to relevant HER2+ tumor models in vivo since trastuzumab also promotes antibody-directed cell cytotoxicity [ 44 – 46 ].…”

Section: Discussionmentioning

confidence: 99%

Endophilin A2 promotes HER2 internalization and sensitivity to trastuzumab-based therapy in HER2-positive breast cancers

2017

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BackgroundHuman epidermal growth factor receptor-2 (HER2) is amplified and a clinical target in a subset of human breast cancers with high rates of metastasis. Targeted therapies involving the antibody trastuzumab and trastuzumab-emtansine (T-DM1) have greatly improved outcomes for HER2-positive (HER2+) breast cancer patients. However, resistance to these targeted therapies can develop and limit their efficacy. Here, we test the involvement of the endocytic adaptor protein endophilin A2 (Endo II) in HER2+ breast cancer models, and their responses to treatments with trastuzumab and T-DM1.MethodsEndo II expression in human breast tumors and lymph node metastases were analyzed by immunohistochemistry. Stable silencing of Endo II was achieved in HER2+ cancer cell lines (SK-BR-3 and HCC1954) to test Endo II effects on HER2 levels, localization and signaling, cell motility and tumor metastasis. The effects of Endo II silencing on the responses of HER2+ cancer cells to trastuzumab or T-DM1 treatments were tested using real-time cell motility and cytotoxicity assays.ResultsHigh Endo II protein expression was detected in HER2-positive tumors, and was linked to worse overall survival in node-positive HER2+ breast cancers at the mRNA level. Stable silencing of Endo II in HER2+ cell lines led to elevated levels of HER2 on the cell surface, impaired epidermal growth factor-induced HER2 internalization, and reduced signaling to downstream effector kinases Akt and Erk. Endo II silencing also led to decreased migration and invasion of HER2+ cancer cells in vitro, and impaired lung seeding following tail vein injection in mice. In addition, Endo II silencing also impaired HER2 internalization in response to Trastuzumab, and led to reduced cytotoxicity response in HER2+ cancer cells treated with T-DM1.ConclusionsOur study provides novel evidence of Endo II function in HER2+ cancer cell motility and trafficking of HER2 that relates to effective treatments with trastuzumab or T-DM1. Thus, differential expression of Endo II may relate to sensitivity or resistance to trastuzumab-based therapies for HER2+ cancers.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-017-0900-z) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Endophilin A2 promotes HER2 internalization and sensitivity to trastuzumab-based therapy in HER2-positive breast cancers

2017

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“…The effect of RAS on ATG12 requires MAP2K/MEK activity RAS promotes tumor growth by binding and activating proteins, such as the protein kinases RAF and the lipid kinase PI3K. 5 We found that treatment of IEC-ras cells with the PI3K inhibitor LY294002 67 blocked phosphorylation of the PI3K effector AKT which is normally observed when the inhibitor is used 68 but did not increase ATG12 levels in these cells which indicates that the effect of RAS on ATG12 in these cells is PI3K-independent (Fig. 9).…”

Section: Oncogenic Ras Reduces Atg12 Protein Stability In Intestinal mentioning

confidence: 72%

“…In an effort to confirm the role of MAP2K in the regulation of ATG12 expression by RAS in cancer cells by a genetic approach we found that IEC-ras cells, when infected with a retrovirus encoding a dominant-negative MAP2K1 mutant, 68 displayed significantly higher levels of total MAP2K (due to the presence of both the endogenous MAP2K and the exogenous dominant-negative MAP2K1 mutant which was not epitopetagged), and noticeably higher free ATG12 levels than the control cells (Fig. 10G).…”

Section: Oncogenic Ras Reduces Atg12 Protein Stability In Intestinal mentioning

confidence: 99%

Oncogenic RAS-induced downregulation of ATG12 is required for survival of malignant intestinal epithelial cells

et al. 2017

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Activating mutations of RAS GTPase contribute to the progression of many cancers, including colorectal carcinoma. So far, attempts to develop treatments of mutant RAS-carrying cancers have been unsuccessful due to insufficient understanding of the salient mechanisms of RAS signaling. We found that RAS downregulates the protein ATG12 in colon cancer cells. ATG12 is a mediator of autophagy, a process of degradation and reutilization of cellular components. In addition, ATG12 can kill cells via autophagy-independent mechanisms. We established that RAS reduces ATG12 levels in cancer cells by accelerating its proteasomal degradation. We further observed that RAS-dependent ATG12 loss in these cells is mediated by protein kinases MAP2K/MEK and MAPK1/ERK2-MAPK3/ERK1, known effectors of RAS. We also demonstrated that the reversal of the effect of RAS on ATG12 achieved by the expression of exogenous ATG12 in cancer cells triggers both apoptotic and nonapoptotic signals and efficiently kills the cells. ATG12 is known to promote autophagy by forming covalent complexes with other autophagy mediators, such as ATG5. We found that the ability of ATG12 to kill oncogenic RAS-carrying malignant cells does not require covalent binding of ATG12 to other proteins. In summary, we have identified a novel mechanism by which oncogenic RAS promotes survival of malignant intestinal epithelial cells. This mechanism is driven by RAS-dependent loss of ATG12 in these cells.

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“…Mechanisms by which ErbB2 promotes three-dimensional growth of breast cancer cells are understood in part. One such mechanism has emerged from our work [ 26 ]. We found that ErbB2 blocks anoikis of breast cancer cells by downregulationg a protein Perp that triggers apoptosis by an unknown mechanism.…”

Section: Introductionmentioning

confidence: 99%

“…Of note, it is known that detachment of non-malignant breast epithelial cells triggers lysosmal degradation of an ErbB2 signalling partner EGFR and that ErbB2-induced Mek activation prevents this degradation in detached breast cancer cells [ 27 ]. We observed that the effect of ErbB2/Mek on EGFR is required for ErbB2-induced Perp downregulation in the indicated cells [ 26 ].…”

Section: Introductionmentioning

confidence: 99%

Mek activity is required for ErbB2 expression in breast cancer cells detached from the extracellular matrix

2017

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Detachment of non-malignant epithelial cells from the extracellullar matrix (ECM) triggers their growth arrest and apoptosis. Conversely, carcinoma cells can grow without adhesion to the ECM. This capacity for anchorage-independent growth is thought to be critical for tumor progression. ErbB2/Her2 oncoprotein is overproduced by a significant fraction of breast cancers and promotes anchorage-independent tumor cell growth by poorly understood mechanisms. In an effort to understand them we found that in order to produce ErbB2, detached breast cancer cells require the activity of an ErbB2 effector protein kinase Mek and that Mek-driven ErbB2 expression is neccesary for anchorage-independent growth of such cells. We observed that Mek inhibition does not alter ErbB2 mRNA levels in detached cancer cells and that ErbB2 protein loss induced by this inhibition can be blocked by a lysosomal inhibitor. We also noticed that an increase of the density of cancer cells detached from the ECM downregulates a Mek effector protein kinase Erk and causes ErbB2 loss. Those cells that survive after ErbB2 loss display resistance to trastuzumab, an anti-ErbB2 antibody used for ErbB2-positive breast cancer treatment. Thus, Mek-induced ErbB2 stabilization in detached breast cancer cells is critical for their ability to grow anchorage-independently and their trastuzumab sensitivity.

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ErbB2-dependent downregulation of a pro-apoptotic protein Perp is required for oncogenic transformation of breast epithelial cells

Cited by 20 publications

References 57 publications

Endophilin A2 promotes HER2 internalization and sensitivity to trastuzumab-based therapy in HER2-positive breast cancers

Endophilin A2 promotes HER2 internalization and sensitivity to trastuzumab-based therapy in HER2-positive breast cancers

Oncogenic RAS-induced downregulation of ATG12 is required for survival of malignant intestinal epithelial cells

Mek activity is required for ErbB2 expression in breast cancer cells detached from the extracellular matrix

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