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PURPOSE: In this study, we aimed at profiling of luminal B breast cancer specific gene expression pattern in Indian women using mRNA-seq and validation based on TCGA expression data. METHODS: RNA isolated from luminal B tumor and adjacent normal tissues was used for library construction and sequencing. Reference-based assemblies of these reads were used for differential gene expression analysis using DeSeq2. The DEGs were evaluated using TCGA expression data. Kaplan-Meier survival method was used to evaluate association between genes showing luminal B specific differential expression pattern and breast cancer prognosis and statistical significance was assessed using log-rank test. Alternate splicing analysis was done using rmats. RESULTS: Differential expression analysis identified 2371 differentially expressed genes (DEGs) in luminal B breast tumors in comparison with adjacent normal tissues of Indian Women. Of them, 1692 DEGs were validated using TCGA luminal B paired samples. Integration of this data with the DEGs obtained by comparative analysis of unpaired luminal B with luminal A unpaired samples from TCGA resulted in 291 DEGs showing luminal B specific expression pattern. Further, 26 genes of prognostic value were identified. Differential splicing analysis between luminal B tumors and adjacent normal tissues in our cohort led to the identification of 687 genes showing significant differential alternate splicing events. CONCLUSION: This study profiled gene expression pattern of luminal B tumors of Indian women and identified 26 key genes of prognostic value for luminal B breast cancer. This study also profiled differential alternate splicing and identified important alternate splicing events in luminal B breast cancer.

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While phenotypic plasticity is a critical factor contributing to tumor heterogeneity, molecular mechanisms underlying this process are largely unknown. Here we report that breast cancer cells display phenotypic diversity in response to hypoxia or normoxia microenvironments by operating a reciprocal positive feedback regulation of HPIP and HIF-1α. We show that under hypoxia, HIF-1α induces HPIP expression that establishes cell survival, and also promotes cell migration/invasion, EMT and metastatic phenotypes in breast cancer cells. Mechanistic studies revealed that HPIP interacts with SRP14, a component of signal recognition particle, and stimulates MMP9 synthesis under hypoxic stress. Whereas, in normoxia, HPIP stabilizes HIF-1α, causing the Warburg effect to support cell growth. Concurrently, mathematical modelling corroborates this reciprocal feedback loop in enabling cell-state transitions in cancer cells. Clinical data indicate that elevated levels of HPIP and HIF-1α correlate with unfavorable prognosis and shorter survival rates in breast cancer subjects. Together, this data shows a reciprocal positive feedback loop between HPIP and HIF-1α that was unknown hitherto. It unveils how the tumor microenvironment influences phenotypic plasticity that has an impact on tumor growth and metastasis and, further signifies considering this pathway as a potential therapeutic target in breast cancer.

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While cancer cells rewire metabolic pathways to sustain growth and survival under metabolic stress in solid tumors, the molecular mechanisms underlying these processes remain largely unknown. In this study, cancer cells switched from survival to death during the early to late phases of metabolic stress by employing a novel signaling switch from AMP activated protein kinase (AMPK)-Forkhead box O3 (FOXO3a)-hematopoietic PBX1-interacting protein (HPIP) to the ring finger protein 2 (RNF2)-HPIP-ubiquitin (Ub) pathway. Acute metabolic stress induced proto-oncogene HPIP expression in an AMPK-FOXO3a-dependent manner in breast cancer (BC) cells. HPIP depletion reduced cell survival and tumor formation in mouse xenografts, which was accompanied by diminished intracellular ATP levels and increased apoptosis in BC cells in response to metabolic (glucose) stress. Glutamine flux (13C-labeled) analysis further suggested that HPIP rewired glutamine metabolism by controlling the expression of the solute carrier family 1 member 5 (SLC1A5) and glutaminase (GLS) genes by acting as a coactivator of MYC to ensure cell survival upon glucose deprivation. However, in response to chronic glucose stress, HPIP was ubiquitinated by the E3-Ub ligase, RNF2, and was concomitantly degraded by the proteasome-mediated pathway, ensuring apoptosis. In support of these data, clinical analyses further indicated that elevated levels of HPIP correlated with AMPK activation in BC. Taken together, these data suggest that HPIP is a signal coordinator during metabolic stress and thus serves as a potential therapeutic target in BC.

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BACKGROUND: Extracellular matrix degradation by matrix metalloproteinases (MMPs) is an important mechanism involved in tumor invasion and metastasis. Genetic variations of MMPs have shown association with multiple cancers. The present study is focused to elucidate the association of MMP-1, 3 and 9 genetic variants with respect to epidemiological and clinicopathological variables by haplotype, LD, MDR, survival in silico analyses among South Indian women. MATERIAL AND METHODS: MMP3-1171 5A/6A and MMP9-1562 C/T SNPs were genotyped by Allele specific polymerase chain reaction and MMP1-1607 1G/2G polymorphism by restriction fragment length polymorphism assays respectively, in 300 BC patients and age-matched 300 healthy controls. Statistical analysis was performed using the SNPStats and SPSS software. Linkage disequilibrium and gene-gene interactions were performed using Haploview and MDR software respectively. Further, transcription factor binding sites in the promoter regions of SNPs under study were carried out using AliBaba2.1 software. RESULTS: We have observed an increased frequency of 2G-allele of MMP1, 6A-allele of MMP3 and T-allele of MMP9 (p<0.05) respectively in BC subjects. The 2G-6A haplotype (minor alleles of MMP-1 and MMP-3 respectively) has shown an increased susceptibility to BC. Further, MMP polymorphisms were associated with the clinical characteristics of BC patients such as steroid hormone receptor status, lymph node involvement and metastasis. SNP combinations were in perfect LD in controls. MDR analysis revealed a positive interaction between the SNPs. 5-years survival rate and cox-regression analysis showed a significant association with clinicopathological variables. CONCLUSION: Our results suggest that MMP1-1607 1G/2G, MMP3-1171 5A/6A and MMP9-1562 C/T gene polymorphisms have synergistic effect on breast cancer. The interactions of MMPs clinical risk factors such as lymph node involvement has shown a strong correlation and might influence the 5-years survival rate, suggesting their potential role in the breast carcinogenesis.

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The aim of this study was to compare the incidence of the different histopathologic types of esophageal carcinoma between the United States of American (US) and India. The Surveillance Epidemiology and End Result (SEER) database was analyzed to determine the incidence of different types of esophageal carcinoma in US. A retrospective review was conducted of all the patients that underwent resection for esophageal carcinoma at a regional oncology center in India from 2001 to 2007. Data relating to histopathologic variables was collected and compared to the patients in the SEER database for the same time period. Esophageal adenocarcinoma accounts for the majority of newly diagnosed cases in the US. Although squamous cell carcinoma is the dominant type of esophageal carcinoma in India, we noted a small but gradual increase (0 % in 2001 to 28 % in 2007) in the incidence of esophageal adenocarcinoma. The results of our study demonstrate a geographic variation in the histopathologic type of esophageal carcinoma. A recent increase in the incidence of esophageal adenocarcinoma in India was also demonstrated. Analysis of risk factors known to be associated with esophageal adenocarcinoma, in the context of India, can provide targets for implementing public health measures.

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BCL2 (B-cell leukemia/lymphoma 2) gene functions as antiapoptotic regulatory element and known to be associated with tumorigenesis. The SNP-938 (C>A) (rs2279115), located in the inhibitory P2 promoter of the BCL2 gene, influences differential binding affinities of transcriptional factors thereby affecting BCL2 expression. The present study is an attempt to evaluate the association between BCL2(-938C>A) polymorphism and clinical characteristics of breast cancer patients as well as to analyze BCL2 expression and Ki67 proliferation index with respect to the genotypes. One hundred ten primary breast cancer tumor tissues were genotyped for -938 C>A polymorphism through PCR-RFLP method as well as evaluated for BCL2 expression and ki67 proliferation index by immunohistochemistry. Evaluation of apoptosis level was performed by flowcytometry. The results revealed that AA genotype was associated with an increased risk (AA Vs AC + CC) by 2.86-fold (p = 0.07) for breast cancer development which reflected in elevated A allele frequency also. AA genotype was found to be predominant among BCL2 positive tumors as compared to BCL2 negative tumors. Further, AA genotype was found to be associated with advanced stage tumors, node positive status, and high Ki67 proliferation index compared to CA and CC genotypes indicating that elevated expression of BCL2 gene in the presence of A allele might be associated with decreased apoptosis and enhanced proliferation rate. AA genotype of BCL2-938C>A polymorphism might influence BCL2 gene expression there by associated with elevated risk for breast cancer progression. Probably, failure of apoptosis due to enhanced expression and antiapoptotic protein BCL2 might promote malignant growth.

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LCN2 (Lipocalin 2) is a 25 KD secreted acute phase protein, reported to be a novel regulator of angiogenesis in breast cancer. Up regulation of LCN2 had been observed in multiple cancers including breast cancer, pancreatic cancer and ovarian cancer. However, the role of LCN2 promoter methylation in the formation of microvessels is poorly understood. The aim of this study was to analyze the association of LCN 2 promoter methylation with microvessel formation and tumor cell proliferation in breast cancer patients. The LCN2 promoter methylation status was studied in 64 breast cancer tumors by methylation specific PCR (MSP). Evaluation of microvessel density (MVD) and Ki67 cell proliferation index was achieved by immunohistochemical staining using CD34 and MIB-1 antibodies, respectively. LCN2 promoter unmethylation status was observed in 43 (67.2%) of breast cancer patients whereas LCN2 methylation status was seen in 21 (32.8%). Further, LCN2 promoter unmethylation status was associated with aggressive tumor phenotype and elevated mean MVD in breast cancer patients.

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This study compared the operative case log experience between rotations during General Surgery residency in the United States and an international rotation in India. A resident from the General Surgery residency program at University of Nebraska Medical Center participated in an international rotation in Surgical Oncology at Mehdi Nawaz Jung Institute of Oncology in Hyderabad, India for 3 months in 2009. The operative case log of this resident (INT) was compared to those of another resident (US) on a rotation in surgical oncology at the parent institution during the same time period. Both institutions were tertiary care centers. We noted that the INT resident performed a greater number of cases (132) when compared to the US resident (61). The INT resident also performed cases in a wider variety of disease categories such as: head and neck (26 %), gynecology (19 %), breast (14 %) and urology (4 %). In contrast, abdominal cases accounted for 68 % of the cases performed by the US resident with fewer cases in the other categories. The INT resident performed 98 % of the cases by the open approach, whereas the US resident performed only 81 % of cases by the open approach, with the remaining 19 % of cases performed by the laparoscopic approach. The results demonstrate that the INT resident performed a greater number of operative cases when compared to a resident (US) at the parent institution, and performed cases in more diverse disease categories with an emphasis on the open operative approach.