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
Source: PubMed


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.

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    ABSTRACT: Background: 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). Methods: 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. Results: 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. Conclusion: 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
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    • "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 [10]. PAD enzymes are highly homologous, with ~50–60 percent sequence identity at the amino acid level. "
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    09/2012; 2012(5):895343. DOI:10.1155/2012/895343
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    06/2015; 4:26192. DOI:10.3402/jev.v4.26192
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