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.

ErbB2-driven downregulation of the transcription factor Irf6 in breast epithelial cells is required for their 3D growth

“…We further found that a published derivative of MCF10A cells, MCF-MekDD, which we generated by infection of MCF10A cells with a retrovirus encoding an activated mutant of Mek (an Erk activator), displays significantly lower Irf6 levels than the parental MCF10A cells in 3D culture (Fig. 5 b) [ 39 ]. Thus, Mek activation is sufficient for Irf6 downregulation in breast epithelial cells detached from the ECM.…”

FOXA1 is required for ErbB2 expression and luminal differentiation in HER2-positive breast cancer

“…2M) (27). Additionally, gene sets liked to HER2 signaling activation, including “AKT_UP.V1_UP” (enrichment score = -0.485, adjusted p-value = 0.027) and “MEK_UP.V1_UP” (enrichment score = -0.465, adjusted p-value = 0.027), were also significantly enriched (28, 29), demonstrating that FOXA1 knockdown inhibited cell growth and survival pathways typically activated downstream of HER2. Conversely, our analysis revealed an enrichment in the “ERBB2_UP.V1_DN” gene set (enrichment score = 0.436, adjusted p-value = 0.021).…”