Chromosomal Alterations Associated with the Transition from In Situ to Invasive Breast Cancer
Clinical Breast Care Project, Henry M. Jakcon Foundation for the Advancement of Military Medicine, 620 Seventh Street, Windber, PA 15963, USA. Annals of Surgical Oncology
(Impact Factor: 3.93).
07/2008; 15(9):2519-25. DOI: 10.1245/s10434-008-0051-7
Ductal carcinoma in situ (DCIS) is a preinvasive lesion of the breast with an inherent but nonobligatory tendency for progression to invasive breast cancer. Although the transition from in situ to invasive disease is critical to the development of breast cancer, molecular and biological changes responsible for this transition are not well characterized.
Chromosomal alterations at 26 regions were assayed in 66 DCIS lesions and 111 invasive ductal carcinomas. Levels and patterns of allelic imbalance (AI) were compared between grade 1 DCIS and well-differentiated breast carcinomas, and between grade 3 DCIS and poorly differentiated invasive breast carcinomas, using Fisher's exact and Student's t-tests.
Levels of AI were significantly lower (P < 0.01) in grade 1 DCIS (11.9%) compared to well-differentiated carcinomas (19.2%), but were not significantly different between grade 3 DCIS and poorly differentiated tumors. No significant differences were detected at any of the 26 chromosomal regions between low-grade DCIS and invasive tumors; however, AI events at chromosomes 1p36, 11q23, and 16q11-q22 could discriminate high-grade in situ from invasive disease.
Lower levels of AI in low-grade in situ compared with invasive disease may reflect the protracted time to progression associated with low-grade DCIS. Increased levels of AI at chromosomes 1p36 and 11q23 in poorly differentiated carcinomas may harbor genes associated with invasiveness, while loss of chromosome 16q11-q22 may prevent the transition from in situ to invasive disease. Further characterization of these changes may provide molecular assays to identify DCIS lesions with invasive potential as well as targets for molecular therapeutics.
Available from: Benedikta S Haflidadóttir
- "The tumour suppressor miR-34c has been shown to be downregulated in a number of different malignancies, such as neuroblastoma (Cole et al, 2008), breast (Yu et al, 2012), lung (Liang, 2008; Liu et al, 2009) and colorectal cancer (Toyota et al, 2008). Downregulation of miR-34c has been suggested to occur due to, for example, loss of heterozygosity within the 11q23 region (Dahiya et al, 1997; Ellsworth et al, 2008), epigenetic events such as CpG island methylation (Toyota et al, 2008; Corney et al, 2010; Vogt et al, 2011) or lost transcriptional induction of p53 (Bommer et al, 2007; Corney et al, 2007; He et al, 2007), as a consequence of p53 often being mutated in advanced cancer (Lane and Levine, 2010). This miRNA is involved in the regulation of proliferation, apoptosis, stem cell renewal, migration, senescence, and chemotherapy resistance (Bommer et al, 2007; Corney et al, 2007; Migliore et al, 2008; Catuogno et al, 2012). "
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The microRNA, miR-34c, is a well-established regulator of tumour suppression. It is downregulated in most forms of cancers and inhibits malignant growth by repressing genes involved in processes such as proliferation, anti-apoptosis, stemness, and migration. We have previously reported downregulation and tumour suppressive properties for miR-34c in prostate cancer (PCa).
In this study, we set out to further characterize the mechanisms by which miR-34c deregulation contributes to PCa progression. The genes regulated by miR-34c in the PCa cell line PC3 were identified by microarray analyses and were found to be enriched in cell death, cell cycle, cellular growth, and cellular movement pathways. One of the identified targets was MET, a receptor tyrosine kinase activated by hepatocyte growth factor, that is crucial for metastatic progression.
We confirmed the inhibitory effect of miR-34c on both MET transcript and protein levels. The binding of miR-34c to two binding sites in the 3′-UTR of MET was validated using luciferase reporter assays and target site blockers. The effect of this regulation on the miR-34c inhibition of the migratory phenotype was also confirmed. In addition, a significant inverse correlation between miR-34c expression levels and MET immunostaining was found in PCa patients.
These findings provide a novel molecular mechanism of MET regulation in PCa and contribute to the increasing evidence that miR-34c has a key tumour suppressive role in PCa.
British Journal of Cancer 08/2013; 109(5). DOI:10.1038/bjc.2013.449 · 4.84 Impact Factor
Available from: John L McElwee
- "The PAD genes likely arose by duplication of the ancestral homologue, PAD2, and are localized to a well-organized gene cluster at 1p36.13 in humans. Interestingly, this locus is also predicted to contain a novel, yet to be defined, tumor suppressor protein . PAD enzymes are highly homologous, with ~50–60 percent sequence identity at the amino acid level. "
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ABSTRACT: The peptidylarginine deiminases (PADs) are a family of posttranslational modification enzymes that catalyze the conversion of positively charged protein-bound arginine and methylarginine residues to the uncharged, nonstandard amino acid citrulline. This enzymatic activity is referred to as citrullination or, alternatively, deimination. Citrullination can significantly affect biochemical pathways by altering the structure and function of target proteins. Five mammalian PAD family members (PADs 1-4 and 6) have been described and show tissue-specific distribution. Recent reviews on PADs have focused on their role in autoimmune diseases. Here, we will discuss the potential role of PADs in tumor progression and tumor-associated inflammation. In the context of cancer, increasing clinical evidence suggests that PAD4 (and possibly PAD2) has important roles in tumor progression. The link between PADs and cancer is strengthened by recent findings showing that treatment of cell lines and mice with PAD inhibitors significantly suppresses tumor growth and, interestingly, inflammatory symptoms. At the molecular level, transcription factors, coregulators, and histones are functional targets for citrullination by PADs, and citrullination of these targets can affect gene expression in multiple tumor cell lines. Next generation isozyme-specific PAD inhibitors may have therapeutic potential to regulate both the inflammatory tumor microenvironment and tumor cell growth.
09/2012; 2012(5):895343. DOI:10.1155/2012/895343
Available from: Anthony P Nicholas
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ABSTRACT: Protein deimination, defined as the post-translational conversion of protein-bound arginine to citrulline, is carried out by a family of 5 calcium-dependent enzymes, the peptidylarginine deiminases (PADs) and has been linked to various cancers. Cellular microvesicle (MV) release, which is involved in cancer progression, and deimination have not been associated before. We hypothesize that elevated PAD expression, observed in cancers, causes increased MV release in cancer cells and contributes to cancer progression.
We have previously reported that inhibition of MV release sensitizes cancer cells to chemotherapeutic drugs. PAD2 and PAD4, the isozymes expressed in patients with malignant tumours, can be inhibited with the pan-PAD-inhibitor chloramidine (Cl-am). We sought to investigate whether Cl-am can inhibit MV release and whether this pathway could be utilized to further increase the sensitivity of cancer cells to drug-directed treatment.
Prostate cancer cells (PC3) were induced to release high levels of MVs upon BzATP stimulation of P2X7 receptors. Western blotting with the pan-protein deimination antibody F95 was used to detect a range of deiminated proteins in cells stimulated to microvesiculate. Changes in deiminated proteins during microvesiculation were revealed by immunoprecipitation and immunoblotting, and mass spectrometry identified deiminated target proteins with putative roles in microvesiculation.
We report for the first time a novel function of PADs in the biogenesis of MVs in cancer cells. Our results reveal that during the stimulation of prostate cancer cells (PC3) to microvesiculate, PAD2 and PAD4 expression levels and the deimination of cytoskeletal actin are increased. Pharmacological inhibition of PAD enzyme activity using Cl-am significantly reduced MV release and abrogated the deimination of cytoskeletal actin. We demonstrated that combined Cl-am and methotrexate (MTX) treatment of prostate cancer cells increased the cytotoxic effect of MTX synergistically. Refined PAD inhibitors may form part of a novel combination therapy in cancer treatment.
06/2015; 4:26192. DOI:10.3402/jev.v4.26192
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