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Studies of LRIG1 and the ERBB receptor family in breast and colorectal cancer
Umeå University, Faculty of Medicine, Radiation Sciences. Umeå University, Faculty of Medicine, Medical Biosciences.
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.

Place, publisher, year, edition, pages
Umeå: Umeå universitet , 2009. , 78 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1271
Keyword [en]
breast cancer, colorectal cancer, LRIG1, EGFR, ERBB2, invasive margin
Research subject
Oncology
Identifiers
URN: urn:nbn:se:umu:diva-25678ISBN: 978-91-7264-798-5 (print)OAI: oai:DiVA.org:umu-25678DiVA: diva2:233108
Distributor:
Strålningsvetenskaper, 90185, Umeå
Public defence
2009-10-16, Sal 244 Lionssalen, Byggn 7, Norrlands universitetssjukhus, Umeå, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2009-09-28 Created: 2009-08-28 Last updated: 2010-01-18Bibliographically approved
List of papers
1. Increased copy number at 3p14 in breast cancer
Open this publication in new window or tab >>Increased copy number at 3p14 in breast cancer
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2005 (English)In: Breast Cancer Research, ISSN 1465-542X, Vol. 7, no 5, R719-R727 p.Article in journal (Refereed) Published
Keyword
myocardial ischemia, pacing, vectorcardiography, electrocardiography, heart rate, myocardial lactate
National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
urn:nbn:se:umu:diva-14494 (URN)10.1186/bcr1279 (DOI)16168117 (PubMedID)
Available from: 2007-12-04 Created: 2007-12-04 Last updated: 2009-10-13Bibliographically approved
2. Co-incidental increase in gene copy number of ERBB2 and LRIG1 in breast cancer
Open this publication in new window or tab >>Co-incidental increase in gene copy number of ERBB2 and LRIG1 in breast cancer
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2009 (English)In: Breast Cancer Research, ISSN 1465-542X, Vol. 11, no 3, 403- p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:umu:diva-25602 (URN)10.1186/bcr2248 (DOI)19490591 (PubMedID)
Available from: 2009-08-24 Created: 2009-08-24 Last updated: 2010-10-14Bibliographically approved
3. LRIG1 expression in colorectal cancer
Open this publication in new window or tab >>LRIG1 expression in colorectal cancer
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2007 (English)In: Acta Oncologica, ISSN 0284-186X, Vol. 46, no 8, 1118-1122 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:umu:diva-17159 (URN)10.1080/02841860701426823 (DOI)17851870 (PubMedID)
Available from: 2008-01-10 Created: 2008-01-10 Last updated: 2015-03-24Bibliographically approved
4. ErbB 1-4 expression alterations in primary colorectal cancers and their corresponding metastases
Open this publication in new window or tab >>ErbB 1-4 expression alterations in primary colorectal cancers and their corresponding metastases
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2009 (English)In: Anticancer Research, ISSN 0250-7005, Vol. 29, no 5, 1489-1494 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: EGFR (epidermal growth factor receptor) targeted therapies are important new tools in colorectal cancer treatment. EGFR analysis of the primary tumour was previously recommended to identify patients who will benefit from the EGFR targeted therapy. Previous studies have displayed diverging results regarding the expression of EGFR in the primary tumour compared to the metastases. The present study was performed to investigate whether EGFR and ErbB2-4 expression differed between 64 primary tumours and their corresponding metastases.

PATIENTS AND METHODS: EGFR and ErbB2-4 expression were analysed in the primary tumour and in the corresponding metastases using immunohistochemistry (IHC).

RESULTS: In 49/64 samples (76%), the primary tumours were EGFR positive; in 33% (16/49) of EGFR positive samples, the tumours lost the EGFR expression in the metastasis compared to the primary tumour. From the primary tumours, 15/64 (23%) were negative and 5 of these (33%) developed EGFR expression in the metastasis. ErbB2, ErbB3, and ErbB4 expression was evident in 54%, 67%, and 81%, respectively. There was no significant difference between ErbB2, ErbB3, and ErbB4 expression in primary tumours and metastases. The co-expression of the ErbB family members was also analysed, with a significant increase of ErbB3/ErbB4 co-expression in late stage tumours.

CONCLUSION: The EGFR expression was lost in 33% of metastasising primary colorectal cancer tumours, a finding that agrees with at least one previous study. Thus, the present results clearly implicate the need for EGFR analysis of both the primary tumour and metastases to accurately determine EGFR status when considering the use of EGFR targeted therapies.

Identifiers
urn:nbn:se:umu:diva-22979 (URN)19443355 (PubMedID)
Available from: 2009-05-25 Created: 2009-05-25 Last updated: 2015-03-24Bibliographically approved
5. Increased EGFR expression at the invasive margin is a negative prognostic factor in colorectal cancer
Open this publication in new window or tab >>Increased EGFR expression at the invasive margin is a negative prognostic factor in colorectal cancer
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(English)Manuscript (preprint) (Other academic)
Keyword
EGFR, colorectal, invasive margin
Identifiers
urn:nbn:se:umu:diva-25601 (URN)
Available from: 2009-08-24 Created: 2009-08-24 Last updated: 2010-01-14Bibliographically approved

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