HER-2 is a potential target of cancer immunotherapy. Anti-HER-2 antibodies have been detected in breast cancer patients (Disis M. et al., 1994) and anti-HER-2 cytotoxic T-lymphocytes have been isolated from breast cancer patients (Peoples G.E. et al., 1995). Protection against mammary tumor growth was observed in mice after vaccination with a full-length, modified human HER-2 DNA (Wei W.-Z. et al., 1999).
Cell lines:
- Several breast cancer cell lines (including SK-BR-3 and AU-565) contain an amplified ERBB2 gene (Kraus M.H. et al., 1987).
- The chemically-induced differentiation of AU-565 and MCF-7 cells is associated with loss of cell surface HER-2 antigen (Bacus S.S. et al., 1990).
- The growth factor heregulin-ß1 (HRG-ß1) enhanced the aggregation of MCF-7, SK-BR-3, MDA-MB-231, and MDA-MB-435 breast cancer cells. HRG-ß1 induced tyrosine phosphorylation of erbB2/erbB3 heterodimers and their association with the 85-kDa subunit of phosphatidylinositol 3-kinase (PI3K). PI3K activation by HRG-ß1 appeared to mediate the aggregative effect of this molecule (Tan M. et al., 1999).
- The phenotypic characteristics of 2 tumor cell lines (BC-H1 and BC-K1) established from bone marrow of patients with breast cancer were studied by immunocytochemistry, flow cytometry, and RT-PCR. Both cell lines expressed
E-cadherin,
vimentin, cytokeratins (including
component 18), alpha 5-,
alpha V-,
beta 1-, and
beta 3- integrin subunits,
ICAM-1,
MCAM, LFA-3 (CD58), and
CD44s (but not
CD44v5,
v6,
v7/8). BC-H1 also expressed ErbB2 (not found in BC-K1), and
MAGE-4 (but not MAGE-1, -2, -3/6, -12; BC-K1 was not tested). The expressed molecules might be potential candidates for novel therapeutic targets (Putz E. et al., 1999).
- The enforced expression of heregulin (HRG) in SK-BR-3 BCC was shown to induce dramatic morphological changes and pronounced inhibition of anchorage-dependent and -independent growth. Most SK BR-3/HRG-transfected (SK/HRG) cells exhibited about 15-fold increase in size and persisted as multinucleated cells with extended flattened vacuole-filled cytoplasm with reduced cell attachment. The growth suppression of SK/HRG cells was accompanied by a reduction in S phase, the presence of a G2-M cell cycle delay, and an increase in DNA aneuploid components. In addition, DNA fragmentation assays showed that HRG induced apoptosis of SK- BR-3 cells. In contrast, while HRG treatment of other erbB-2 overexpressing BCC lines led to growth arrest and cell detachment, it did not induce apoptotic features (Guerra-Vladusic F.K. et al., 1999).
- A 17-bp-long cis sequence located between positions -506 and -489 from the transcription start site of HER-2/neu was found to be recognized by a trans-activating factor named HER-2 transcription factor (HTF). This factor, involved in the increased transcription of the HER2 gene in the BT-474 mammary tumor cells, has a molecular weight of about Mr 50,000. HTF could also bind, but with a lower affinity, to a related cis sequence present in the
epidermal growth factor receptor promoter. Interestingly, the HTF binding activity is high in nuclear extracts from several mammary tumor cells overexpressing the HER2 gene (Grooteclaes M. et al., 1999).
Tumors:
- HER-2 and
GRB-7 are frequently co-amplified and overexpressed (Stein D. et al., 1994).
- Abundant levels of c-erbB-2 mRNA have been found in tumours exhibiting membrane staining for c-erbB-2 and these levels correlated with the percentage of tumour cells showing membranous staining for c-erbB-2. However, the level of c-erbB-2 mRNA in tumours displaying only cytoplasmic staining was no higher than in c-erbB-2-negative specimens (Taylor S.L. et al., 1998).
- In a comparative study of 61 cytology specimen (obtained by fine-needle sampling) and 47 corresponding frozen sections of breast carcinomas, cytology specimen appeared to be a suitable and representative source of materials for detection and quantitation of HER-2/neu gene amplification by fluorescent in situ hybridization (FISH) and image analysis (Klijanienko J. et al., 1999).
- Different epitopes on the extracellular domain of HER-2 can serve as distinct targets for immunotoxins. Studies aim to determine the optimal epitope target for immunotoxin therapy (Boyer C.M. et al., 1999).
- Protection against mammary tumor growth has been obtained by vaccination with full-length, modified human
ErbB-2 DNA (Wei W.-Z. et al., 1999).
- The tyrosine kinase inhibitor emodin significantly inhibited tumor growth and prolonged survival in mice bearing HER-2/neu-overexpressing human breast cancer cells. Furthermore, the combination of emodin and paclitaxel, a commonly used chemotherapeutic agent for breast cancer patients, synergistically inhibited the anchorage-dependent and -independent growth of HER-2/neu-overexpressing breast cancer cells
in vitro and synergistically inhibited tumor growth and prolonged survival in athymic mice bearing s.c. xenografts of human tumor cells expressing high levels of p185neu. Both immunohistochemical staining and Western blot analysis showed that emodin decreases tyrosine phosphorylation of HER-2/neu in tumor tissue (Zhang L. et al., 1999).
