Role of HER2 gene overexpression in breast carcinoma

Abstract

The HER2 proto-oncogene encodes a transmembrane glycoprotein of 185 kDa (p185(HER2)) with intrinsic tyrosine kinase activity. Amplification of the HER2 gene and overexpression of its product induce cell transformation. Numerous studies have demonstrated the prognostic relevance of p185(HER2), which is overexpressed in 10% to 40% of human breast tumors. Recent data suggest that p185(HER2) is a ligand orphan receptor that amplifies the signal provided by other receptors of the HER family by heterodimerizing with them. Ligand-dependent activation of HER1, HER3, and HER4 by EGF or heregulin results in heterodimerization and, thereby, HER2 activation. HER2 overexpression is associated with breast cancer patient responsiveness to doxorubicin, to cyclophosphamide, methotrexate, and fluorouracil (CMF), and to paclitaxel, whereas tamoxifen was found to be ineffective and even detrimental in patients with HER2-positive tumors. In vitro analyses have shown that the role of HER2 overexpression in determining the sensitivity of cancer cells to drugs is complex, and molecules involved in its signaling pathway are probably the actual protagonists of the sensitivity to drugs. The association of HER2 overexpression with human tumors, its extracellular accessibility, as well as its involvement in tumor aggressiveness are all factors that make this receptor an appropriate target for tumor-specific therapies. A number of approaches are being investigated as possible therapeutic strategies that target HER2: (1) growth inhibitory antibodies, which can be used alone or in combination with standard chemotherapeutics; (2) tyrosine kinase inhibitors (TKI), which have been developed in an effort to block receptor activity because phosphorylation is the key event leading to activation and initiation of the signaling pathway; and (3) active immunotherapy, because the HER2 oncoprotein is immunogenic in some breast carcinoma patients.

Humoral Immunity Directed against Tumor-Associated Antigens As Potential Biomarkers for the Early Diagnosis of Cancer

“…Protein overexpression occurs in approximately 30% of breast cancers, particularly premenopausal breast cancer, and is associated with more aggressive disease and a poor prognosis in patients with positive lymph nodes. 41 Similar to investigations of antibody response to p53, endogenous humoral immunity to HER-2/neu directly correlates to overexpression of the protein by the patient's tumor, and HER-2/neu-specific autoantibodies can be detected in patients with early stage disease, indicating that the presence of antibodies are not simply a reflection of tumor burden. HER-2/neu antibodies at titers of >1:100 were detected in 12 of 107 (11%) breast cancer patients versus 0 of 200 (0%) controls (p < 0.01).…”

Biologic and therapeutic role of HER2 in cancer

“…Various clinical studies have evaluated the relationship between HER2 and breast cancer outcome, and most have shown that women with HER2-positive tumors have a poorer prognosis than women with HER2-negative tumors (Me´nard et al, 2000(Me´nard et al, , 2001bMasood and Bui, 2002). However, while the prognostic value of HER2 amplification/overexpression in node-positive patients has been widely demonstrated, there is no consensus on its value in node-negative cases (Press et al, 1997;Ross et al, 1998;Volpi et al, 2000;Cooke et al, 2001).…”

Fhit Expression Protects Against HER2-Driven Breast tumor Development: Unraveling the Molecular Interconnections

“…[45][46][47] These two receptors stand at the origin of the major signaling pathway involved in the growth of breast cancer. EGFR amplification and activating mutations are rare events in breast cancer and differences in EGFR expression appear to be controlled largely at the transcriptional level.…”