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

ABSTRACT: 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.

SUBMITTER: Khan IA

PROVIDER: S-EPMC5739645 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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

Khan Iman A IA Yoo Byong H BH Rak Janusz J Rosen Kirill V KV

Oncotarget 20171031 62

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 th ...[more]

PMID: 29285258

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Project description:BackgroundBreast cancer progression has been gradually recognized as a bidirectional interaction between cancer cells and tumor microenvironment including stroma cells, immune cells, and the dynamically altered ECM. However, there still lacks direct experimental evidences about how ECM properties modulate the activities of stroma and immune cells.MethodThe transcriptomic data and corresponding clinical information of breast cancer pawere obtained from TCGA. Patients were divided into ECM-high, ECM-median and ECM-low groups based on ssGSEA scores of C-ECM genes. The prognostic value of ECM was confirmed by univariate/multivariate Cox regression and survival analyses. GO and KEGG analyses were performed between ECM-high and -low groups. Then associations between ECM characteristics and clinical stages were verified by Masson's trichrome and Sirius red/Fast Green staining of clinical breast cancer tissues. To evaluate the effects of ECM on CAF induction and T cell activation, the MRC-5, NIH/3T-3, primary T cells and Jurkat T cells were encapsulated in 3D collagen with different densities and organizations, and the expression levels of CAF biomarkers and secretion levels of IL-2 were assessed.ResultsECM scores showed broad variation across paracancerous and cancer samples as well as breast cancer molecular subtypes, and patients with different ECM groups showed distinct prognosis. Immunological activity and ECM associated biology processes were identified by GO and KEGG analyses across ECM-high and -low groups. According to MCP-counter algorithm, the infiltration of T cells was significantly lower in the ECM-high group, while CAF abundance was significantly higher. It is furtherly confirmed by clinical samples that collagen density and organization were associate with breast cancer progression. Finally, in vitro 3D-cultured fibroblasts and T cells validated that the density and organization of collagen showed significant effects on CAF induction and T cell activation.ConclusionOur study revealed a new mechanism of T cell immunosuppression and CAF induction, which could be of central importance for the breast cancer invasion and may constitute novel therapeutic targets to improve breast cancer outcomes.

Dataset Information

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

Publications

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

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