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High cell-surface density of HER2 deforms cell membranes

Inhee Chung¹, Mike Reichelt², Lily Shao³

¹Molecular Oncology, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.

Nature Communications

|September 8, 2016

Abstract:

Breast cancers (BC) with HER2 overexpression (referred to as HER2 positive) progress more aggressively than those with normal expression. Targeted therapies against HER2 can successfully delay the progression of HER2-positive BC, but details of how this overexpression drives the disease are not fully understood. Using single-molecule biophysical approaches, we discovered a new effect of HER2 overexpression on disease-relevant cell biological changes in these BC. We found HER2 overexpression causes deformation of the cell membranes, and this in turn disrupts epithelial features by perturbing cell-substrate and cell-cell contacts. This membrane deformation does not require receptor signalling activities, but results from the high levels of HER2 on the cell surface. Our finding suggests that early-stage morphological alterations of HER2-positive BC cells during cancer progression can occur in a physical and signalling-independent manner.

Insights

Overexpression of HER2 in breast cancer (BC) causes cell membrane deformation, disrupting cell contacts and promoting aggressive disease progression through physical, signaling-independent mechanisms.

Area of Science:

Biophysics
Cell Biology
Oncology

Background:

HER2 overexpression drives aggressive breast cancer (BC) progression.
Targeted therapies exist, but the underlying mechanisms of HER2-driven BC are not fully understood.

Purpose of the Study:

To investigate the biophysical effects of HER2 overexpression on BC cell morphology and behavior.
To elucidate the signaling-independent contributions of HER2 to BC progression.

Main Methods:

Single-molecule biophysical approaches.
Analysis of cell membrane deformation and cell-cell/cell-substrate contacts in HER2-positive BC cells.

Main Results:

HER2 overexpression induces significant cell membrane deformation.
This deformation disrupts epithelial features by altering cell-substrate and cell-cell contacts.
Membrane deformation occurs independently of HER2 receptor signaling activities.

Conclusions:

Physical changes in cell membranes due to high HER2 levels contribute to BC progression.
Early-stage morphological alterations in HER2-positive BC can be driven by physical, signaling-independent mechanisms.

Read full analysis

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