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1.
Oncogene ; 34(18): 2309-16, 2015 Apr 30.
Article in English | MEDLINE | ID: mdl-24954507

ABSTRACT

Crosstalk between estrogen receptor (ER) and the inflammatory nuclear factor κB (NFκB) pathway in ER+ breast cancers may contribute to a more aggressive phenotype. Pleckstrin Homology-Like Domain, Family A, member 1 (PHLDA1), a target gene of ER-NFκB crosstalk, has been implicated in cell survival and stem cell properties. 17ß-estradiol (E2), acting through ERα, and pro-inflammatory cytokines, acting through NFκB, increase the nascent transcript and PHLDA1 messenger RNA stability, indicating both transcriptional and post-transcriptional control of PHLDA1 expression. We show that PHLDA1 is a direct target of miR-181 and that mature miR-181a and b, as well as their host gene, are synergistically downregulated by E2 and tumor necrosis factor α, also in an ER- and NFκB-dependent manner. Thus, ER and NFκB work together to upregulate PHLDA1 directly through enhanced transcription and indirectly through repression of miR-181a and b. Previous studies have suggested that PHLDA1 may be a stem cell marker in the human intestine that contributes to tumorigenesis. Our findings that PHLDA1 is upregulated in mammospheres (MS) of ER+ breast cancer cells and that PHLDA1 knockdown impairs both MS formation and the expansion of aldehyde dehydrogenase (ALDH)-positive population, suggest that PHLDA1 may play a similar role in breast cancer cells. Upregulation of PHLDA1 in MS is largely dependent on the NFκB pathway, with downregulated miR-181 expression a contributing factor. Over-expression of miR-181 phenocopied PHLDA1 knockdown and significantly impaired MS formation, which was reversed, in part, by protection of the PHLDA1 3' untranslated region (UTR) or overexpression of PHLDA1 lacking the 3'UTR. Furthermore, we find that elevated PHLDA1 expression is associated with a higher risk of distant metastasis in ER+ breast cancer patients. Altogether, these data suggest that high PHLDA1 expression is controlled through an ER-NFκB-miR-181 regulatory axis and may contribute to a poor clinical outcome in patients with ER+ breast tumors by enhancing stem-like properties in these tumors.


Subject(s)
Breast Neoplasms/pathology , MicroRNAs/genetics , NF-kappa B/metabolism , Receptors, Estrogen/metabolism , Transcription Factors/metabolism , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Cell Line, Tumor , Female , Gene Expression Regulation, Neoplastic , Humans , MCF-7 Cells , Neoplastic Stem Cells/metabolism , Signal Transduction , Transcription Factors/genetics
4.
Pharmacogenomics J ; 10(5): 458-64, 2010 Oct.
Article in English | MEDLINE | ID: mdl-20177422

ABSTRACT

There is increasing evidence that the Let-7 microRNA (miRNA) exerts an effect as a tumor suppressor by targeting the KRAS mRNA. The Let-7 complementary site (LCS6) T>G variant in the KRAS 3'-untranslated region weakens Let-7 binding. We analyzed whether the LCS6 variant may be clinically relevant to patients with metastatic colorectal cancer (MCRC) treated with anti-epidermal growth factor receptor (EGFR) therapy. LCS6 genotypes and KRAS/BRAF mutations were determined in the tumor DNA of 134 patients with MCRC who underwent salvage cetuximab-irinotecan therapy. There were 34 G-allele (T/G+G/G) carriers (25%) and 100 T/T genotype carriers (75%). G-allele carriers were significantly more frequent in the KRAS mutation group than in patients with KRAS wild type (P=0.004). In the 121 patients without BRAF V600E mutation, overall survival (OS) and progression-free survival (PFS) times were compared between carriers of the LCS6 G-allele genotypes and carriers of the wild-type T/T genotype. LCS6 G-allele carriers showed worse OS (P=0.001) and PFS (P=0.004) than T/T genotype carriers (confirmed in the multivariate model including the KRAS status). In the exploratory analysis of the 55 unresponsive patients with KRAS mutation, LCS6 G-allele carriers showed adverse OS and PFS times. These findings deserve additional investigations as they may open novel perspectives for the treatment of patients with MCRC.


Subject(s)
3' Untranslated Regions , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/drug therapy , MicroRNAs/genetics , Proto-Oncogene Proteins/genetics , Salvage Therapy , ras Proteins/genetics , Adult , Aged , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Camptothecin/administration & dosage , Camptothecin/analogs & derivatives , Camptothecin/therapeutic use , Cetuximab , Cohort Studies , Colorectal Neoplasms/genetics , Colorectal Neoplasms/mortality , Colorectal Neoplasms/pathology , Disease-Free Survival , Female , Genotype , Humans , Irinotecan , Male , Middle Aged , Neoplasm Metastasis , Proto-Oncogene Proteins p21(ras) , Retrospective Studies
5.
Br J Cancer ; 101(4): 715-21, 2009 Aug 18.
Article in English | MEDLINE | ID: mdl-19603018

ABSTRACT

BACKGROUND: KRAS codons 12 and 13 mutations predict resistance to anti-EGFR monoclonal antibodies (moAbs) in metastatic colorectal cancer. Also, BRAF V600E mutation has been associated with resistance. Additional KRAS mutations are described in CRC. METHODS: We investigated the role of KRAS codons 61 and 146 and BRAF V600E mutations in predicting resistance to cetuximab plus irinotecan in a cohort of KRAS codons 12 and 13 wild-type patients. RESULTS: Among 87 KRAS codons 12 and 13 wild-type patients, KRAS codons 61 and 146 were mutated in 7 and 1 case, respectively. None of mutated patients responded vs 22 of 68 wild type (P=0.096). Eleven patients were not evaluable. KRAS mutations were associated with shorter progression-free survival (PFS, HR: 0.46, P=0.028). None of 13 BRAF-mutated patients responded vs 24 of 74 BRAF wild type (P=0.016). BRAF mutation was associated with a trend towards shorter PFS (HR: 0.59, P=0.073). In the subgroup of BRAF wild-type patients, KRAS codons 61/146 mutations determined a lower response rate (0 vs 37%, P=0.047) and worse PFS (HR: 0.45, P=0.023). Patients bearing KRAS or BRAF mutations had poorer response rate (0 vs 37%, P=0.0005) and PFS (HR: 0.51, P=0.006) compared with KRAS and BRAF wild-type patients. CONCLUSION: Assessing KRAS codons 61/146 and BRAF V600E mutations might help optimising the selection of the candidate patients to receive anti-EGFR moAbs.


Subject(s)
Adenocarcinoma/genetics , Biomarkers, Tumor/genetics , Colorectal Neoplasms/genetics , Drug Resistance, Neoplasm/genetics , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins/genetics , ras Proteins/genetics , Adenocarcinoma/pathology , Adult , Aged , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Camptothecin/administration & dosage , Camptothecin/analogs & derivatives , Cetuximab , Codon , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/pathology , DNA Mutational Analysis , Disease-Free Survival , ErbB Receptors/metabolism , Female , Humans , Irinotecan , Kaplan-Meier Estimate , Male , Middle Aged , Mutation , Proto-Oncogene Proteins p21(ras)
6.
Pharmacogenomics J ; 9(1): 78-84, 2009 Feb.
Article in English | MEDLINE | ID: mdl-19104506

ABSTRACT

The interleukin-1 receptor antagonist (IL-1RA) cytokine is thought to counteract tumor angiogenesis/metastasis. Two single nucleotide polymorphisms in the IL-1RA gene (rs4251961 T/C and rs579543 C/T) influence IL-1RA circulating levels with highest production in carriers of the homozygous rs4251961 T/T and rs579543 T/T genotypes. A total of 180 patients with metastatic colorectal cancer were categorized as high IL-1RA producers if they were carriers of at least one of the rs4251961 T/T or rs579543 T/T genotypes (T/T carriers). Median survival times were 35.8 months (95% confidence interval: 29.7-43.7 months) and 28.6 months (95% confidence interval: 25.6-30 months) in 56 T/T carriers and in 124 non-T/T carriers, respectively. The favorable association between T/T carriers' status and survival was significant in the multivariate analysis (P=0.018). Also, T/T carriers and non-T/T carriers were prevalent among patients with Karnofsky performance status 90-100 and 70-80, respectively (P=0.002). These findings encourage additional studies in this field and the evaluation of a recombinant-IL-1RA for anticancer activity.


Subject(s)
Colorectal Neoplasms/genetics , Interleukin 1 Receptor Antagonist Protein/genetics , Polymorphism, Single Nucleotide , Aged , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized , Antineoplastic Agents/therapeutic use , Cetuximab , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/mortality , Colorectal Neoplasms/surgery , Disease-Free Survival , Female , Genotype , Humans , Interleukin 1 Receptor Antagonist Protein/blood , Karnofsky Performance Status , Male , Middle Aged , Multivariate Analysis , Neoplasm Invasiveness
7.
Br J Cancer ; 99(5): 716-21, 2008 Sep 02.
Article in English | MEDLINE | ID: mdl-18728661

ABSTRACT

We investigated the association between thymidylate synthase (TS) germline polymorphisms and response to 5-fluorouracil-based chemotherapy in 80 patients with liver-only metastatic colorectal cancer (MCRC). The tandem repeat polymorphism (VNTR) in TS 5'-untranslated region (5'-UTR), which consists of two (2R) or three (3R) 28-bp repeated sequences, with or without a G/C nucleotide change in 3R carriers (3G or 3C) and a 6-bp insertion/deletion (6+/6-) in the TS 3'-UTR, was studied. The distinction between high (2R/3G, 3C/3G and 3G/3G) and low (2R/2R, 2R/3C and 3C/3C) TS expression genotypes according to the 5'-UTR VNTR+G/C nucleotide change showed significant association with tumour response (P=0.01). In particular, high TS expression genotypes were found in 8 out of 34 patients (23.5%) with complete or partial response and in 24 out of 46 patients (52%) with stable disease and disease progression. Liver-only MCRC patients are a homogeneous and clinical relevant subgroup that may represent an ideal setting for studying the actual influence of TS polymorphisms.


Subject(s)
Antimetabolites, Antineoplastic/therapeutic use , Colorectal Neoplasms/drug therapy , Fluorouracil/therapeutic use , Liver Neoplasms/secondary , Polymorphism, Genetic , Thymidylate Synthase/genetics , Colorectal Neoplasms/enzymology , Colorectal Neoplasms/pathology , Female , Genotype , Haplotypes , Humans , Liver Neoplasms/drug therapy , Liver Neoplasms/enzymology , Male , Survival Analysis , Tandem Repeat Sequences , Treatment Outcome
8.
Pharmacogenomics J ; 8(4): 278-88, 2008 Aug.
Article in English | MEDLINE | ID: mdl-17549067

ABSTRACT

The primary end point of the study was the analysis of associations between polymorphisms with putative influence on 5-fluorouracil/irinotecan activity and progression-free survival (PFS) of patients with advanced colorectal cancer treated with first-line FOLFIRI chemotherapy. Peripheral blood samples from 146 prospectively enrolled patients were used for genotyping polymorphisms in thymidylate synthase (TS), methylenetetrahydrofolate reductase (MTHFR), excision repair cross-complementation group-1 (ERCC 1) xeroderma pigmentosum group-D (XPD), X-ray cross-complementing-1 (XRCC 1), X-ray cross-complementing-3 (XRCC 3) and uridine diphosphate-glucuronosyltransferases-A1 (UGT1 A1). TS 3'-UTR 6+/6+ and XRCC3-241 C/C genotypes were associated with adverse PFS. Hazard ratio for PFS achieved 2.89 (95% confidence interval=1.56-5.80; P=0.002) in 30 patients (20%) with both risk genotypes. Risk for Grade III-IV neutropenia was significantly associated with UGT1A1*28 7/7 genotype. These promising findings deserve further investigations and their validation in independent prospective studies.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , Gene Expression Profiling/methods , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Camptothecin/analogs & derivatives , Camptothecin/pharmacology , Camptothecin/therapeutic use , Disease-Free Survival , Female , Fluorouracil/pharmacology , Fluorouracil/therapeutic use , Genotype , Humans , Irinotecan , Leucovorin/pharmacology , Leucovorin/therapeutic use , Male , Middle Aged , Pharmacogenetics/methods , Polymorphism, Genetic/drug effects , Polymorphism, Genetic/genetics , Prospective Studies
9.
Ann Oncol ; 16(6): 887-92, 2005 Jun.
Article in English | MEDLINE | ID: mdl-15851404

ABSTRACT

BACKGROUND: Polymorphisms in the interleukin 1beta gene (IL-1B-31T/C and IL-1B-511C/T single nucleotide changes) and in the interleukin 1 receptor anatagonist gene (IL-1RN2 variable number of tandem repeats) have been studied with respect to gastric cancer susceptibility. Available data support an aetiologic role of these genetic variants in the presence of concomitant Helicobacter pylori infection. Their contribution without H. pylori infection is still an open field of investigation. MATERIALS AND METHODS: IL-1B and IL-1RN polymorphisms were investigated in 138 H. pylori-negative Italian patients with sporadic gastric cancer and 100 H. pylori-negative controls. Unconditional regression with odd ratios (OR) and 95% confidence intervals (CI), haplotype and linkage disequilibrium analyses were used to investigate the association of the polymorphisms with disease. RESULTS: In all gastric cancer cases, carriers of the homozygous IL-1B-511T/T genotype showed a significant risk for the development of the disease (OR 3.2 with 95% CI 1.27-8.05). In cases with intestinal-type gastric cancer, however, both IL-1B-511T and IL-1RN2 alleles were associated with disease. In this subgroup, the odds ratio for carriers of both IL-1B-511T and IL-1RN2 was 6.49 (95% CI 2.07-20.4). Haplotype analysis supported the aetiologic contribution of these alleles in gastric cancer of the intestinal histotype. CONCLUSIONS: In conclusion, IL-1B-511T and IL-1RN2 may contribute to intestinal gastric cancer risk in the absence of concomitant H. pylori infection. In this setting, future epidemiologic studies should consider dietary habits and exposure to carcinogens interacting with pro-inflammatory host genotypes.


Subject(s)
Helicobacter pylori/isolation & purification , Interleukin-1/genetics , Polymorphism, Genetic , Sialoglycoproteins/genetics , Stomach Neoplasms/genetics , Adult , Aged , Aged, 80 and over , Case-Control Studies , Female , Haplotypes , Humans , Interleukin 1 Receptor Antagonist Protein , Male , Middle Aged , Risk , Stomach Neoplasms/etiology , Stomach Neoplasms/microbiology , Stomach Neoplasms/pathology
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