Oncotarget

Research Papers:

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

Iman A. Khan, Byong H. Yoo, Janusz Rak and Kirill V. Rosen _

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Oncotarget. 2017; 8:105383-105396. https://doi.org/10.18632/oncotarget.22194

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Abstract

Iman A. Khan1, Byong H. Yoo2, Janusz Rak3,4 and Kirill V. Rosen1,2

1Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, Canada

2Department of Pediatrics, Dalhousie University, Halifax, Canada

3Department of Pediatrics, McGill University, Montreal, Canada

4The Research Institute of the McGill University Health Centre, Montreal Children’s Hospital, Montreal, Canada

Correspondence to:

Kirill V. Rosen, email: kirill.rosen@dal.ca

Keywords: extracellular matrix; three-dimensional tumor growth; ErbB2; Mek; trastuzumab

Received: June 27, 2017    Accepted: September 09, 2017    Published: October 31, 2017

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.


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