Studies of LRIG1 and the ERBB receptor family in breast and colorectal cancer

Sammanfattning: The LRIG1 gene (leucine-rich repeats and immunoglobulin like domains-1) at chromosome 3p14 is a proposed tumour suppressor gene whose gene product negatively regulates various receptor tyrosine kinases. This function has been the basis for classifying LRIG1 as a potential tumour suppressor gene (TSG). The ERBB receptor family is important in malignant cellular functions such as proliferation, survival, adhesion, migration and differentiation. In breast cancer, amplification of the ERBB2 proto-oncogene is an important negative prognostic factor. The epidermal growth factor receptor (EGFR/ERBB1), is expressed in colorectal cancer and has been correlated to a worse prognosis. Until recently, immunohistochemical analysis of EGFR expression was used to select patients suitable for treatment with EGFR targeted antibodies.This thesis characterizes LRIG1 in breast and colorectal cancer to gain further knowledge of the gene and its expression. Also, the EGFR expression in metastases and the invasive margin of colorectal cancers was investigated to correlate changes to clinical factors. Breast cancer samples and matched normal tissues were evaluated for LRIG1 and the ERBB receptors at gene, RNA and protein levels. An increase in copy number of the LRIG1 gene was evident. Also, increased LRIG1 copy number was associated with high levels of ERBB2 mRNA. Another set of breast cancer tumours were analysed for LRIG1 by FISH analysis. The results were coherent with the previous results. To further analyze the correlation to ERBB2, tumours with LRIG1 increased copy number were analysed for ERBB2. The data showed that 89% of tumours with increased LRIG1 copy number were either ERBB2 amplified or had an increased copy number of ERBB2.To investigate LRIG1 and the EGFR in colorectal cancer, the gene and protein expression was analysed by several methods in tumours and corresponding normal tissues. There were no significant changes at gene level found, but at the protein level, both over- and under expression were seen. No evident correlation between LRIG1 and EGFR expression was detected.The ERBB receptor family expression in colorectal cancer tumours and corresponding metastases was investigated to explore if the expression was altered in the metastatic lesion. The results showed that the EGFR expression was lost in the corresponding metastases in 33% of the tumours and that the same percentage of tumours gained expression in the metastases. Co-expression of the ERBB family members was also analysed; there was a significant increase of ERBB3/ERBB4 co-expression in late stage tumours. EGFR expression at the invasive margin of colorectal cancers was analysed to clarify whether expression correlated to the patient’s prognosis. Significant correlation to survival and the presence of budding was seen.In conclusion, 34% of the breast cancer tumours studied had an increased copy number of LRIG1 with a significant co-incidental increase in ERBB2 copy number. This raises the question of a functional correlation between LRIG1 and ERBB2, a finding that might be of clinical importance. The studies of EGFR and the ERBB receptors in colorectal cancer reflect the heterogeneity of EGFR expression in tumours. In addition, these findings suggest that survival of the patients correlates to an increasing EGFR expression at the invasive margin.