Amplification of the HER-2 gene occurs in approximately 25% of breast cancers, causing up-regulation of key signaling pathways which control cell growth and survival. In breast cancer patients, HER-2 overexpression correlates with an aggressive phenotype and poor prognosis. HER-2, therefore, has become the focus of many anti-cancer therapeutic approaches. Trastuzumab (Herceptin), a humanized monoclonal antibody directed against the extracellular domain of HER-2, was the first FDA-approved HER-2-targeted therapy for the treatment of metastatic breast cancer. However, not all HER-2-overexpressing patients respond to trastuzumab and most that initially respond develop resistance within one year of treatment. Trastuzumab resistance has been studied in cell line models of resistance and several mechanisms of resistance have been proposed. More recent anti-HER-2 strategies involve targeting its tyrosine kinase domain; for example, lapatinib (Tykerb) is a dual HER-2 and EGFR tyrosine kinase inhibitor and has shown efficacy as a single agent and in combination with other therapeutics. A number of novel HER-2 antagonists are currently in preclinical or clinical development, including both monoclonal antibodies and small molecule inhibitors. Increased understanding of HER-2 signaling in breast cancer, and of response and resistance to HER-2 antagonists, will aid the development of strategies to overcome resistance to HER-2 targeted therapies.
"Herceptin (Trastuzumab), a humanized monoclonal antibody targeting HER-2/neu, has shown some benefit as a treatment for patients with HER-2/neu-expressing breast cancer, but clinical studies show that patients with high levels of HER-2/neu who are treated with a single dose of Herceptin progress to metastatic disease within one year –. The potential mechanisms underlying Herceptin failure are found in altered EGFR receptors, increased Akt activity and IGF-IR signaling, reduced p27kip1 and PTEN level in breast cancer cell , . "
[Show abstract][Hide abstract] ABSTRACT: Herceptin failure is a major clinical problem in breast cancer. A subset of breast cancer patients with high HER-2/neu levels eventually experience metastatic disease progression when treated with Herceptin as a single agent. Mechanistic details of development of this aggressive disease are not clear. Therefore, there is a dire need to better understand the mechanisms by which drug resistance develops and to design new combined treatments that benefit patients with aggressive breast cancer and have minimal toxicity. We hypothesized that 3, 3'-diindolylmethane (DIM), a non-toxic agent can be combined with Herceptin to treat breast cancers with high levels of HER-2/neu. Here, we evaluated the effects of Herceptin alone and in combination with DIM on cell viability, apoptosis and clonogenic assays in SKBR3 (HER-2/neu-expressing) and MDA-MB-468 (HER-2/neu negative) breast cancer cells. We found that DIM could enhance the effectiveness of Herceptin by significantly reducing cell viability, which was associated with apoptosis-induction and significant inhibition of colony formation, compared with single agent treatment. These results were consistent with the down-regulation of Akt and NF-kB p65. Mechanistic investigations revealed a significant upregulation of miR-200 and reduction of FoxM1 expression in DIM and Herceptin-treated breast cancer cells. We, therefore, transfected cells with pre-miR-200 or silenced FoxM1 in these cells for understanding the molecular mechanism involved. These results provide experimental evidence, for the first time, that DIM plus Herceptin therapy could be translated to the clinic as a therapeutic modality to improve treatment outcome of patients with breast cancer, particularly for the patients whose tumors express high levels of HER-2/neu.
PLoS ONE 01/2013; 8(1):e54657. DOI:10.1371/journal.pone.0054657 · 3.23 Impact Factor
"trastuzumab) and therefore has limited treatment options. Similarly, in the HER-2 positive subtype, only 30–50% of patients respond to trastuzumab and even then, these patients often develop resistance over time , . For prostate cancer, an estimated 211,000 men will be diagnosed with prostate cancer this year in North America and 33,000 men will die from the disease , . "
[Show abstract][Hide abstract] ABSTRACT: The Y-box binding protein-1 (YB-1) is an oncogenic transcription/translation factor that is activated by phosphorylation at S102 whereby it induces the expression of growth promoting genes such as EGFR and HER-2. We recently illustrated by an in vitro kinase assay that a novel peptide to YB-1 was highly phosphorylated by the serine/threonine p90 S6 kinases RSK-1 and RSK-2, and to a lesser degree PKCα and AKT. Herein, we sought to develop this decoy cell permeable peptide (CPP) as a cancer therapeutic. This 9-mer was designed as an interference peptide that would prevent endogenous YB-1S102 phosphorylation based on molecular docking. In cancer cells, the CPP blocked P-YB-1S102 and down-regulated both HER-2 and EGFR transcript level and protein expression. Further, the CPP prevented YB-1 from binding to the EGFR promoter in a gel shift assay. Notably, the growth of breast (SUM149, MDA-MB-453, AU565) and prostate (PC3, LNCap) cancer cells was inhibited by ∼90% with the CPP. Further, treatment with this peptide enhanced sensitivity and overcame resistance to trastuzumab in cells expressing amplified HER-2. By contrast, the CPP had no inhibitory effect on the growth of normal immortalized breast epithelial (184htert) cells, primary breast epithelial cells, nor did it inhibit differentiation of hematopoietic progenitors. These data collectively suggest that the CPP is a novel approach to suppressing the growth of cancer cells while sparing normal cells and thereby establishes a proof-of-concept that blocking YB-1 activation is a new course of cancer therapeutics.
PLoS ONE 09/2010; 5(9). DOI:10.1371/journal.pone.0012661 · 3.23 Impact Factor
"In this section, potential mechanisms of resistance to HER-2 blocking strategies are discussed; the implications of HER-2 overexpression regarding resistance to chemotherapy are dealt with in section 5.3. HER-2 amplification occurs in 15e25% of all breast cancers (Browne et al., 2009; Moelans et al., 2010). The seminal discovery by Dr. Slamon and co-workers (Slamon et al., 1987, 1989) of the prognostic impact of HER-2 amplification in breast cancer lead to development of trastuzumab, a humanized antibody (Ross et al., 2004) targeting HER-2. "
[Show abstract][Hide abstract] ABSTRACT: Chemoresistance remains the main reason for therapeutic failure in breast cancer as well as most other solid tumours. While gene expression profiles related to prognosis have been developed, so far use of such signatures as well as single markers has been of limited value predicting drug resistance. Novel technologies, in particular with regard to high through-put sequencing holds great promises for future identification of the key "driver" mechanisms guiding chemosensitivity versus resistance in breast cancer as well as other malignant conditions.
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