Target-based therapies in breast cancer: current status and future perspectives

Abstract

Identification of molecular alterations in key proteins involved in breast cancer cell proliferation and survival resulted in the development of a new treatment strategy with target-based agents. The anti-ErbB-2 monoclonal antibody (mAb) trastuzumab and the dual epidermal growth factor receptor/ErbB-2 tyrosine kinase inhibitor lapatinib are effective in patients with breast cancer that overexpresses ErbB-2. The anti-vascular endothelial growth factor-A mAb bevacizumab is approved in combination with taxanes for treatment of unselected patients with metastatic breast cancer. In addition, preclinical data suggest that signaling inhibitors can prevent or overcome resistance to endocrine therapy in estrogen receptor positive (ERC) breast cancer. However, the majority of signaling inhibitors explored in breast cancer patients has shown little activity, at least when used as monotherapy; and the results of clinical trials in ERC breast cancer of combinations of signaling inhibitors and endocrine therapies are rather disappointing. Negative findings are likely due to mechanisms of intrinsic or acquired resistance to target-based agents. Breast carcinoma is a complex and heterogeneous disease and several different molecular alterations are involved in its pathogenesis and progression. The redundancy of oncogenic pathways activated in cancer cells, the heterogeneity of the mechanisms of resistance, and the plasticity of tumor cells that are capable to adapt to different growth conditions, significantly hamper the efficacy of each signaling inhibitor in breast cancer. Therefore, a comprehensive approach that takes into account the complexity of the disease is definitely required to improve the efficacy of target-based therapy in breast cancer.

Effects of the combined blockade of EGFR and ErbB-2 on signal transduction and regulation of cell cycle regulatory proteins in breast cancer cells.

“…Interestingly, they found that ErbB-3 activation was dependent on ErbB-2, whose residual kinase activity was able to drive ErbB-3 phosphorylation. Interestingly, acquired resistance to anti-ErbB-2 agents can occur through different mechanisms including increased activation of EGFR signalling [21], suggesting that a cross-talk between these two receptors might limit the activity of target based agents directed against either the EGFR or ErbB-2 in breast cancer patients.…”

“…Contemporary targeting of both EGFR and ErbB-2 can be also accomplished by using tyrosine kinase inhibitors that block the activity of different ErbB-receptors. In this regard, lapatinib is a dual EGFR/ErbB-2 tyrosine kinase inhibitor that has been recently approved for treatment of ErbB-2 expressing patients [21].…”

Targeted Apoptosis in Breast Cancer Immunotherapy

“…The antibody-drug conjugate, Trastuzumab-DM1 is currently in a late clinical trial for treatment of HER2-positive breast cancers (Alley et al, 2010;Senter, 2009). Breast cancer-targeted delivery systems are also constructed by modifying the envelop of viral particles, liposomes or other nanomaterials with tumor cellbinding phage peptides, or with ligands or antibodies that recognize HER2, E-selectin, transferrin or erythropoietin-producing hepatocellular receptor tyrosine kinase receptor class A2 (EphA2) (Alvarez et al, 2010;Mann et al, 2010;Normanno et al, 2009;Sarkar et al, 2005;Tandon et al, 2011). Tumor-specific regulatory elements, such as promoters of human telomerase reverse transcriptase (hTERT), survivin, Muc1 and the homologous recombinationrelated protein Rad51, as well as the hypoxia-responsive elements (HRE) have been employed in the regulation of pro-apoptotic genes like Bax and truncated Bid in the development of breast cancer-targeted therapeutic strategies (Lee, 2009;Kazhdan et al, 2006;Hine et al, 2008).…”

Quercetin inhibits human breast cancer cell proliferation and induces apoptosis via Bcl-2 and Bax regulation

“…Current treatment of breast cancer follows an integrated therapeutic model, which includes surgery, radiation therapy, chemotherapy, endocrine therapy, and biological therapy; this approach has made breast cancer one of the most successfully treatable solid tumors (5). Chemotherapy is irreplaceable in this treatment plan.…”