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.
Highlights
15-20% of breast tumors overproduce ErbB2/ Her2 oncoprotein which drives the progression of these malignancies [1]
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
The effect of selumetinib on ErbB2 was not unique to MCF-ErbB2 cells as we found that the Mek inhibitor downregulates ErbB2 in detached ErbB2positive human breast cancer cell lines BT-474, AU-565 and HCC-1419 [31, 32] but has no effect on ErbB2 levels when these cells are attached to the extracellullar matrix (ECM) (Figure 1B-1D). (Changes in the ErbB2 protein levels observed in Figure 1A-1D are quantified in Supplementary Figure 1)
Summary
15-20% of breast tumors overproduce ErbB2/ Her oncoprotein which drives the progression of these malignancies [1]. One critical feature of primary and disseminated breast tumors, including those overproducing ErbB2, is their ability to grow in a three-dimensional manner [4] Such growth requires the ability of cancer cells to survive without adhesion to the extracellular matrix (ECM) [5]. This notion is based on the fact that normal basal and luminal breast epithelial cells are attached to the ECM in the breast [6, 7]. We show that as the number of detached breast tumor cells composing a three-dimensionally growing cellular mass increases, Mek activity and ErbB2 expression are lost and the resulting ErbB2-deficient cells display resistance to trastuzumab, an anti-ErbB2 antibody normally used for treatment of ErbB2-positive breast cancer. Mekdependent ErbB2 expression in detached breast cancer cells is critical for their ability to grow without adhesion to the ECM and for their trastuzumab sensitivity
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