ABSTRACT
BACKGROUND: Defective DNA repair is central to the progression and treatment of breast cancer. Immunohistochemically detected DNA repair markers may be good candidates for novel prognostic and predictive factors that could guide the selection of individualized treatment strategies. PATIENTS AND METHODS: We have analyzed nuclear immunohistochemical staining of BRCA1, FANCD2, RAD51, XPF, and PAR in relation to clinicopathological and survival data among 1240 paraffin-embedded breast tumors, and additional gene expression microarray data from 76 tumors. The antioxidant enzyme NQO1 was analyzed as a potential modifier of prognostic DNA repair markers. RESULTS: RAD51 [hazard ratio (HR) 0.81, 95% confidence interval (CI) 0.70-0.94, P = 0.0050] and FANCD2 expression (HR 1.50, 95% CI 1.28-1.76, P = 1.50 × 10(-7)) were associated with breast cancer survival. High FANCD2 expression correlated with markers of adverse prognosis but remained independently prognostic in multivariate analysis (HR 1.27, 95% CI 1.08-1.49, P = 0.0043). The FANCD2-associated survival effect was most pronounced in hormone receptor positive, HER2-negative tumors, and in tumors with above-median NQO1 expression. In the NQO1-high subset, patients belonging to the highest quartile of FANCD2 immunohistochemical scores had a threefold increased risk of metastasis or death (HR 3.10, 95% CI 1.96-4.92). Global gene expression analysis indicated that FANCD protein overabundance is associated with the upregulation of proliferation-related genes and a downregulated nucleotide excision repair pathway. CONCLUSION: FANCD2 immunohistochemistry is a sensitive, independent prognostic factor in breast cancer, particularly when standard markers indicate relatively favorable prognosis. Taken together, our results suggest that the prognostic effect is linked to proliferation, DNA damage, and oxidative stress; simultaneous detection of FANCD2 and NQO1 provides additional prognostic value.
Subject(s)
Breast Neoplasms/genetics , Fanconi Anemia Complementation Group D2 Protein/biosynthesis , NAD(P)H Dehydrogenase (Quinone)/biosynthesis , Prognosis , Biomarkers, Tumor , Breast Neoplasms/pathology , DNA Repair/genetics , Fanconi Anemia Complementation Group D2 Protein/genetics , Female , Gene Expression Regulation, Neoplastic , Humans , NAD(P)H Dehydrogenase (Quinone)/genetics , Receptor, ErbB-2/geneticsABSTRACT
BACKGROUND: Most non-small-cell lung cancer (NSCLC) patients receive cisplatin-based chemotherapy though clinical response is restricted to a subset of patients. DNA repair protein levels are possible surrogates for cisplatin-induced DNA adduct (and subsequent cell death) repair efficiency and thus molecular determinants of therapeutic efficacy. The International Adjuvant Lung Trial (IALT)-Bio study previously suggested ERCC1 and MSH2 as predictive of cisplatin-based therapeutic benefit. PATIENTS AND METHODS: DNA repair protein expression (XPF, BRCA1, ERCC1, MSH2, p53, PARP1, and ATM) was assessed by immunohistochemistry on a large subset of patients (N = 769) from the IALT trial. Tissue Microarray slides were digitally scanned and signal quantified by user-defined macros. Statistical analyses (univariate and multivariate) of 5-year disease-free survival (DFS) and 5-year overall survival used binary cut-offs (H score low/high expression). RESULTS: In patients with squamous cell carcinoma (SCC), ATM, p53, PARP1, ERCC1, and MSH2 displayed significant (borderline) predictive values, mainly on DFS with chemotherapy efficacy limited to low marker levels. Adenocarcinoma (ADC) results were not significant. BRCA1 and XPF were not significant for predictive modeling in either SCC or ADCs. CONCLUSION: Here predictive utility of DNA repair enzymes co-segregates with SCC histology, focusing their predictive value to this histological subclass of NSCLC. Distinct mechanisms of chemotherapeutic response or resistance might exist among histological subclasses of solid tumors.
Subject(s)
Adenocarcinoma/metabolism , Antineoplastic Agents/pharmacology , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Squamous Cell/metabolism , Cisplatin/pharmacology , DNA-Binding Proteins/metabolism , Lung Neoplasms/metabolism , Adenocarcinoma/mortality , Adenocarcinoma/pathology , Adenocarcinoma/therapy , Adenocarcinoma of Lung , Aged , Antineoplastic Agents/therapeutic use , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Non-Small-Cell Lung/therapy , Carcinoma, Squamous Cell/mortality , Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/therapy , Chemotherapy, Adjuvant , Cisplatin/therapeutic use , DNA Repair , DNA-Binding Proteins/genetics , Disease-Free Survival , Female , Gene Expression , Humans , Immunohistochemistry , Kaplan-Meier Estimate , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Lung Neoplasms/therapy , Male , Middle Aged , Multivariate Analysis , Prognosis , Randomized Controlled Trials as Topic , Tissue Array Analysis , Treatment OutcomeABSTRACT
The synthesis of 1,4-diamines containing the (Z)-1,4-diaminobut-2-ene subunit via a temporary phosphorus tether/RCM strategy is described. We have developed a new method utilizing phosphorus nuclei as suitable temporary tethers for the coupling of nonracemic allylic amines. This approach allows for the generation of C(2)-symmetric and unsymmetric 1,4-diamines 1-3, which may have considerable synthetic and biological utility. This represents the first synthetic pathway for the expedient coupling of two amines via a temporary tether approach. [structure: see text]
Subject(s)
Diamines/chemistry , Phosphorus/chemistryABSTRACT
The preparation and utilization of C(2)-symmetric 1,4-diamines in the synthesis of amino acid-derived cyclic phosphonamides 1-3 are described. The 1,4-diamines are synthesized via three methods: (i) amino acid/fumaryl chloride coupling followed by amide reduction, (ii) amino acid/1,4-diamine coupling followed by amide reduction, and (iii) a template-supported ring-closing metathesis/hydrolysis sequence. The pseudo C(2)-symmetric cyclic phosphonamides 1-3 are prepared by condensation of the C(2)-symmetric 1,4-diamines to P(III) centers, followed by oxidation.
Subject(s)
HIV Protease Inhibitors/chemical synthesisABSTRACT
The synthesis of an array of P-chiral amino acid-derived phosphonamidic anhydrides is described. These anhydrides are prepared by condensation of allylated amino acids 19-22 with methyl- or vinylphosphonic dichlorides 23 or 24 to produce three diastereomeric anhydrides 4-11a-c in good to excellent yields. The mechanistic issues concerning anhydride formation are discussed and supported by experimental results. Vinylphosphonamidic anhydrides 8-11 are further derivatized via the ring-closing metathesis (RCM) reaction to yield amino acid-derived bicyclic phosphonamidic anhydrides.