Human epidermal growth factor receptor-2 (HER-2) and topoisomerase IIalpha (topo IIalpha) co-inhabit chromosome 17. In the search for predictive biomarkers to refine clinical prescription of cytotoxic agents, both HER-2 and topo IIalpha are under exploration for their potential role in identifying individuals with early breast cancer who may benefit from anthracycline therapy. Whilst recent meta-analyses support a predictive role for HER-2 amplification, it remains unclear whether HER-2 is the critical biomarker or whether it is a surrogate marker for topo IIalpha alteration, a known drug target of anthracyclines. The major limitation in considering HER-2 as a single marker is heterogeneity within the subgroups of HER-2 positive and HER-2 negative disease. For topo IIalpha, current data is inconclusive. Issues plaguing this field are technical variability in marker definition, complex regulation pathway of topo IIalpha and lack of prospective, adequately powered studies. With current evidence, neither HER-2 nor topo IIalpha gene status can be considered clinically valuable markers for anthracycline benefit. This paper will focus on issues relating to reliable detection and predictive analyses of HER-2 and topo IIalpha, and highlight potential developments in improving individualized approach to anthracycline use in early breast cancer patients.
"Major focus has been on human epidermal growth factor receptor 2 (HER2) and topo IIα expression based on their localization in chromosome 17 as well as determinants of sensitivity to trastuzumab and anthracyclines, respectively. Indeed several reports have established expression of topo IIα in predicting sensitivity to adjuvant anthracycline therapy (Oakman et al., 2009; Brase et al., 2010; Kawachi et al., 2010; Di Leo et al., 2011; Du et al., 2011; Nikolényi et al., 2011; O’Malley et al., 2011). The evaluation of tissue inhibitor of metalloproteinase (TIMP-1) with HER2 or topo IIα has also suggested that a HT profile (HER2 amplified and/or TIMP-1 negative) or 2T profile (topo IIα aberrant and/or TIMP-1 negative) with substantial reduction in mortality but not relapse free survival events following adjuvant anthracycline containing therapy (Ejlertsen et al., 2010; Hertel et al., 2012). "
[Show abstract][Hide abstract] ABSTRACT: Inhibitors of topoisomerase II (topo II) are clinically effective in the management of hematological malignancies and solid tumors. The efficacy of anti-tumor drugs targeting topo II is often limited by resistance and studies with in vitro cell culture models have provided several insights on potential mechanisms. Multidrug transporters that are involved in the efflux and consequently reduced cytotoxicity of diverse anti-tumor agents suggest that they play an important role in resistance to clinically active drugs. However, in clinical trials, modulating the multidrug-resistant phenotype with agents that inhibit the efflux pump has not had an impact. Since reduced drug accumulation per se is insufficient to explain tumor cell resistance to topo II inhibitors several studies have focused on characterizing mechanisms that impact on DNA damage mediated by drugs that target the enzyme. Mammalian topo IIα and topo IIβ isozymes exhibit similar catalytic, but different biologic, activities. Whereas topo IIα is associated with cell division, topo IIβ is involved in differentiation. In addition to site specific mutations that can affect drug-induced topo II-mediated DNA damage, post-translation modification of topo II primarily by phosphorylation can potentially affect enzyme-mediated DNA damage and the downstream cytotoxic response of drugs targeting topo II. Signaling pathways that can affect phosphorylation and changes in intracellular calcium levels/calcium dependent signaling that can regulate site-specific phosphorylation of topoisomerase have an impact on downstream cytotoxic effects of topo II inhibitors. Overall, tumor cell resistance to inhibitors of topo II is a complex process that is orchestrated not only by cellular pharmacokinetics but more importantly by enzymatic alterations that govern the intrinsic drug sensitivity.
Frontiers in Pharmacology 08/2013; 4:89. DOI:10.3389/fphar.2013.00089 · 3.80 Impact Factor
"Epirubicin HCl, a derivative of doxorubicin, leads to the inhibition of DNA and RNA synthesis by intercalation between base pairs of the DNA/RNA. It also inhibits topoisomerase II by stabilizing DNA-topoisomerase complex, resulting in DNA damage and induction of apoptosis and cell death
. It was also proposed that epirubicin could induce formation of reactive oxygen species promoting apoptosis
[Show abstract][Hide abstract] ABSTRACT: Background
Hypoxia is a common characteristic of solid tumors associated with reduced response to radio- and chemotherapy, therefore increasing the probability of tumor recurrence. The aim of this study was to identify new mechanisms responsible for hypoxia-induced resistance in breast cancer cells.
MDA-MB-231 and HepG2 cells were incubated in the presence of taxol or etoposide respectively under normoxia and hypoxia and apoptosis was analysed. A whole transcriptome analysis was performed in order to identify genes whose expression profile was correlated with apoptosis. The effect of gene invalidation using siRNA was studied on drug-induced apoptosis.
MDA-MB-231 cells incubated in the presence of taxol were protected from apoptosis and cell death by hypoxia. We demonstrated that TMEM45A expression was associated with taxol resistance. TMEM45A expression was increased both in MDA-MB-231 human breast cancer cells and in HepG2 human hepatoma cells in conditions where protection of cells against apoptosis induced by chemotherapeutic agents was observed, i.e. under hypoxia in the presence of taxol or etoposide. Moreover, this resistance was suppressed by siRNA-mediated silencing of TMEM45A. Kaplan Meier curve showed an association between high TMEM45A expression and poor prognostic in breast cancer patients. Finally, TMEM45 is highly expressed in normal differentiated keratinocytes both in vitro and in vivo, suggesting that this protein is involved in epithelial functions.
Altogether, our results unravel a new mechanism for taxol and etoposide resistance mediated by TMEM45A. High levels of TMEM45A expression in tumors may be indicative of potential resistance to cancer therapy, making TMEM45A an interesting biomarker for resistance.
BMC Cancer 09/2012; 12(1):391. DOI:10.1186/1471-2407-12-391 · 3.36 Impact Factor
"This theory has been evaluated by retrospective review of TOP2A status and mortality outcomes of patients in randomized controlled trials (RCTs) and cohort studies, and response to treatment in neoadjuvant studies with mixed results in all three types of studies.5,9,10,12–14 Similarly, HER2 status has been correlated with anthracycline response to varying degrees, though reviews of the literature have led some investigators to conclude that anthracycline benefit may not be predicted by HER2 or TOP2A status.15,16 Most recently, Bartlett et al8 proposed that PS17 duplication (CH17CEP) is the strongest predictor of treatment benefit with anthracyclines.8 "
[Show abstract][Hide abstract] ABSTRACT: Human epidermal growth factor receptor 2 (HER2)/neu, topoisomerase II alpha (TOP2A), and polysomy 17 may predict tumor responsiveness to doxorubicin (DOX) therapy.
We identified neoadjuvant DOX/cyclophosphamide treated breast cancer patients in our registry from 1997 to 2008 with sufficient tissue for testing (n = 34). Fluorescence in situ hybridization (FISH) testing was done on deparaffinized tissue sections pretreated using vendor's standard protocol modification, and incubated with US Food and Drug Administration approved Abbott Diagnostics Vysis PathVysion™ probe set, including Spectrum-Green-conjugated probe to α-satellite DNA located at the centromere of chromosome 17 (17p11.1-q11.1) and a Spectrum-Orange-conjugated probe to the TOP2A gene. Morphometric analysis was performed using a MetaSystems image analysis system. Manual counting was performed on all samples in which autofluorescence and/or artifact prevented the counting of sufficient numbers of cells. A ratio >2.0 was considered positive for TOP2A amplification. Polysomy 17 (PS17) presence was defined as signals of ≥2.5. Outcomes were pathological complete response (pCR), partial response (PR), and nonresponse (NR).
Of 34 patients tested, one was TOP2A amplified (hormone receptor negative/HER2 negative, partial responder). The subset of TOP2A nonamplified, HER2 negative, and PS17 absent (n = 23) patients had treatment response: pCR = 2 (9%), PR = 14 (61%), and NR = 7 (30%). Including the two PS17 present and HER2-positive patients (n = 33), 76% of TOP2A nonamplified patients had pCR or PR.
We observed substantial treatment response in patients lacking three postulated predictors that would be difficult to attribute to cyclophosphamide alone. Patients who are HER2 negative and lack TOP2A amplification and PS17 should not be excluded from receiving DOX-containing regimens.
Cancer Management and Research 08/2010; 2(1):213-8. DOI:10.2147/CMR.S12849
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