High cell-surface density of HER2 deforms cell membranes.
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.
Molecular Oncology, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.
Inhee
I
Chung
Research Pathology, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.
Mike
M
Reichelt
Translational Oncology, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.
Lily
L
Shao
Molecular Oncology, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.
Robert W
RW
Akita
Research Pathology, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.
Hartmut
H
Koeppen
Research Pathology, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.
Linda
L
Rangell
Translational Oncology, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.
Gabriele
G
Schaefer
Cancer Immunology, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.
Ira
I
Mellman
Molecular Oncology, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.
Mark X
MX
Sliwkowski
D000230:Adenocarcinoma / Q000378:metabolism; D000906:Antibodies; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000502:physiology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D046529:Microscopy, Electron, Transmission / Q000379:methods; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
D000906:Antibodies; D018719:Erb-b2 Receptor Tyrosine Kinases