Cytoplasmic Overexpression of HER2: a Key Factor in Colorectal Cancer

Abstract

Trastuzumab, a humanized mouse monoclonal antibody directed against HER2 (Human Epidermal Growth Factor Receptor 2), is currently a keystone in the treatment of breast cancer. Meanwhile, trastuzumab has been validated for use in other types of cancer too. But the data on HER2 expression in colorectal cancer are ambiguous, with reported overexpression of HER2 varying between zero and 84%. In this review these studies are evaluated and compared. It shows that many factors influence the determination of HER2-expression, especially of the intracellular fraction of HER2. It is concluded that although membranous overexpression of HER2 is low in colorectal cancer with only 5% of all patients being positive, a significant proportion of the patients (30%) shows cytoplasmic HER2 overexpression. The clinical impact of enhanced intracellular HER2 is not known, because the nature and origin have not completely been revealed yet. Enlightening this process could be a stepping stone towards targeting of intracellular HER2 as a treatment option.

Keywords: ErbB2; HER2; Her2/neu; biomarker; colorectal cancer; cytoplasmic; herceptin; immunohistochemistry; membranous; survival; tissue microarray; trastuzumab.

Figure 1

Paraffin-embedded colorectal cancer tissue was incubated with A0485 anti-HER2 antibody with increasing incubation times of 30 minutes, 1 hour, 2 hours and overnight. Note: With longer incubation times, an increase in cytoplasmic staining (brown) can be observed.

Figure 2

A schematic representation of the difference in HER2 expression between multiple cell types. In a normal cell (A), a single copy of the HER2- gene is transcribed to low levels of mRNA, which is then translated to HER2 which enters the endoplasmatic reticulum (ER). In the ER, HER2 is processed (eg, glycosylated), and transported to the Golgi apparatus (GA). There it undergoes final processing before being transported to the membrane. In breast cancer (B), this process is basically identical except that gene amplification leads to higher mRNA and HER2 levels. The processing capacity of the ER is improved, most likely due to the unfolded protein response (UPR). In colorectal cancer however (C), there is no gene amplification, but gene expression is upregulated during transcription. Notes: The ER cannot keep up with the high amount of protein, therefore immature HER2 cannot to be completely processed in the ER, and cannot be transported to the GA and the cell membrane; instead incompletely folded HER2 might be extracted from the ER via the ER associated degradation pathway, deglycosylated into a 155–160 kDa protein prior to it accumulation and ultimately proteasomal degradation in the cytoplasm.