Expression and Amplification of HER3 Gene in Primary Breast Carcinomas

R Naidu PhD^a, AW Norhanom PhD^b, MK Kutty MD^c

^aDepartment of Molecular Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia, ^bInstitute of Biological Sciences, University of Malaya, Kuala Lumpur, Malaysia, ^cSeri Kota Medical Center, Klang, Selangor, Malaysia

AIM: HER3 is a member of the type I receptor tyrosine kinase family which is highly related in structure to HER1 and HER2. Although overexpression of HER3 has been demonstrated in breast, pancreatic, brain, gastric, bladder and prostate cancers, amplification of HER3 gene was rarely observed in these tumors. The purpose of this study is to assess and determine the frequency of HER3 protein overexpression and gene amplification in primary breast carcinomas. METHODS: A series of 291 formalin-fixed paraffin-embedded primary breast carcinoma tissues were investigated for HER3 expression by immunohistochemical method while amplification of HER3 gene was detected using differential polymerase chain reaction (dPCR). Of 291 breast tissues, 13 were non-comedo ductal carcinoma in situ (DCIS), 18 were comedo DCIS, 14 were non-comedo DCIS with adjacent invasive ductal carcinomas (IDC), 28 were comedo DCIS with adjacent IDC, and 218 were IDC. RESULTS: Overexpression and amplification of HER3 were detected in 46% and 12% of 291 primary breast carcinomas, respectively. HER3 expression was elevated in 29% of the DCIS, 28% of the DCIS and 43% of the adjacent IDC, and 49% of the IDC. HER3 was amplified only in 10% of the DCIS, 12% of the DCIS and adjacent IDC, and 12% of the IDC. Based on DCIS subtypes, HER3 was overexpressed in 15% of non-comedo DCIS, 39% of comedo DCIS, 14% of non-comedo DCIS and 29% of the adjacent IDC, and 36% of comedo DCIS and 50% of the adjacent IDC. Amplification of HER3 gene was found in 17% of comedo DCIS, and 18% of comedo DCIS and adjacent IDC. HER3 amplification was not identified in non-comedo DCIS, and noncomedo-invasive carcinomas. The tumors positive for HER3 immunostaining and gene amplification in the in situ lesions showed similar pattern of staining and amplification in the adjacent invasive components. All the tumors with HER3 amplification showed elevated levels of HER3 protein. CONCLUSIONS: HER3 protein is overexpressed more frequently than HER3 gene amplification in primary breast carcinomas suggesting that other mechanisms may be responsible for the activation of HER3 gene. Although overexpression and amplification of HER3 are often detected in comedo DCIS as well as comedo DCIS with adjacent invasive lesions, the occurrence of these abnormalities are much higher in invasive than in situ carcinomas. Overexpression and amplification of HER3 gene in preinvasive, preinvasive and adjacent invasive carcinomas and invasive carcinomas suggest that HER3 may have an important role in early and late stages of breast cancer development. Furthermore, HER3 could also be involved in the progression of tumors from non-invasive to invasive stage.

Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Nice, France; February 7 - 10, 2004; in poster session 797 (Manifestations of cancer).