Exercise has been shown to reduce risk and improve prognosis of several types of cancers. Irisin is a myokine linked to exercise and lean body mass, which is thought to favorably alter metabolism systemically, potentially providing benefit for metabolic disease (including cancer). We evaluated the effects of various concentrations of irisin (with and without posttranslational modifications) on malignant and non-malignant breast epithelial cell number, migration and viability. Irisin significantly decreased cell number, migration and viability in malignant MDA-MB-231 cells, without affecting non-malignant MCF10a cells. Moreover, irisin enhanced the cytotoxic effect of doxorubicin (Dox) when added to a wide spectrum of irisin concentrations in the malignant cell type (with simultaneous reduction in Dox uptake), which was not observed in non-malignant MCF-10a cells. Additionally, we found that irisin decreases malignant cell viability in part through stimulation of caspase activity leading to apoptotic death. Interestingly, we found that irisin suppresses NFjB activation, an opposite effect of other myokines such as tumor necrosis factor alpha (TNF-a). Our observations suggest that irisin may offer therapeutic benefits for breast cancer prevention and treatment possibly through an anti-inflammatory response, induction of apoptotic cell death, or through enhanced tumor sensitivity to common antineoplastic agents such as Dox.

Cancer arises from an accumulation of mutations that promote the selection of cells with progressively malignant phenotypes. Previous studies have shown that genomic instability, a hallmark of cancer cells, is a driving force in this process. In the present study, two markers of genomic instability, telomere DNA content and allelic imbalance, were examined in two independent cohorts of mammary carcinomas. Altered telomeres and unbalanced allelic loci were present in both tumors and surrounding histologically normal tissues at distances at least 1 cm from the visible tumor margins. Although the extent of these genetic changes decreases as a function of the distance from the visible tumor margin, unbalanced loci are conserved between the surrounding tissues and the tumors, implying cellular clonal evolution. Our results are in agreement with the concepts of ''field cancerization'' and ''cancer field effect,'' concepts that were previously introduced to describe areas within tissues consisting of histologically normal, yet genetically aberrant, cells that represent fertile grounds for tumorigenesis. The finding that genomic instability occurs in fields of histologically normal tissues surrounding the tumor is of clinical importance, as it has implications for the definition of appropriate tumor margins and the assessment of recurrence risk factors in the context of breast-sparing surgery. ' 2006 Wiley-Liss, Inc.Key words: telomere loss; allelic imbalance; genomic instability; cancer field effect; breast cancer Genomic instability is an important factor in the progression of human cancers. [1][2][3][4] One mechanism that underlies genomic instability is loss of telomere function. [5][6][7] Telomeres are nucleoprotein complexes located at the ends of eukaryotic chromosomes. Telomeres in human somatic cells are composed of 1,000 to 2,000 tandemly repeated copies of the hexanucleotide DNA sequence, TTAGGG. 8 Numerous telomere binding proteins are associated with these repeat regions and are important for telomere maintenance. 9,10 Telomeres stabilize chromosome ends and prevent them from being recognized by the cell as DNA double-strand breaks, thereby preventing degradation and recombination. 11 However, telomeres can be critically shortened, and thereby become dysfunctional, by several mechanisms, including incomplete replication of the lagging strand during DNA synthesis, 12 loss or alterations of telomere-binding proteins involved in telomere maintenance, 13 and oxidative stress leading to DNA damage. 14 Alternatively, telomere loss may be compensated for by recombination 15,16 or, as seen in the majority of human cancers, by the enzyme telomerase. 17,18 Telomeres in tumors are frequently shorter than in the matched adjacent normal tissues, presumably reflecting their extensive replicative histories. [19][20][21] The cause-and-effect relation between dysfunctional telomeres and genomic instability implies that shortened telomeres are also associated with altered gene expression. The latter is a primary source of p...