Mammary epithelial cells constitutively expressing Id-1 protein are unable to differentiate, acquire the ability to proliferate, and invade the extracellular matrix. In addition, Id-1 is aberrantly over-expressed in aggressive and metastatic breast cancer cells, as well as in human breast tumor biopsies from infiltrating carcinomas, suggesting Id-1 might be an important regulator of breast cancer progression. We show that human metastatic breast cancer cells become significantly less invasive in vitro and less metastatic in vivo when Id-1 is downregulated by stable transduction with antisense Id-1. Expression of the matrix metalloproteinase MT1-MMP is decreased in proportion to the decrease in Id-1 protein levels, representing a potential mechanism for the reduction of invasiveness. Further, to more accurately recapitulate the biology of and potential therapeutic approaches to tumor metastasis, we targeted Id-1 expression systemically in tumorbearing mice by using a nonviral approach. We demonstrate significant reduction of both Id-1 and MT1-MMP expressions as well as the metastatic spread of 4T1 breast cancer cells in syngeneic BALB͞c mice. In conclusion, our studies have identified Id-1 as a critical regulator of breast cancer progression and suggest the feasibility of developing novel therapeutic approaches to target Id-1 expression to reduce breast cancer metastasis in humans.T he Id (inhibitor of DNA binding) genes were originally identified in murine myoblasts, where they prevented myogenic basic helix-loop-helix (bHLH) transcription factors from binding muscle-specific regulatory elements (1). These transcription factors are key regulators of tissue-specific gene expression in a number of mammalian and nonmammalian organisms, and constitutive expression of Id proteins has been shown to inhibit the differentiation of various tissues (2). bHLH proteins act as obligate dimers, dimerizing through HLH domains, and bind to DNA through the composite basic domains to activate the transcription of target genes containing E-boxes (CANNTG) in their promoters. Id proteins dimerize with bHLH proteins, but the Id-bHLH heterodimers fail to bind to DNA because Id proteins lack the basic domains necessary for DNA interaction.Four members of the Id gene family have been described to date: Id-1, . The different family members localize to different chromosomes and show marked differences in their pattern of expression and function (3, 4). Although the family members are similar in the HLH sequence, the regions outside the HLH domain are distinct for each member and may determine the tissue specificity of Id function, as well as the binding specificity for particular bHLH proteins.We previously developed a line of murine mammary epithelial cells (MEC), SCp2 cells, which originated from a midpregnant mouse mammary gland (5, 6). A role for HLH Id proteins in the differentiation of SCp2 cells was suggested by our finding that Id-1 expression declined to undetectable levels when the cells were induced to differentiate in culture ...

The expression of many genes is altered in colon cancer, but the roles of these genes in carcinogenesis are unclear. Using real-time quantitative PCR, we demonstrated that several genes previously implicated in human colon cancer undergo altered expression in the APC min mouse adenomatous polyp, a precursor of cancer, as well as in normal-appearing surrounding mucosa. The five genes that were most highly up-regulated in mouse polyp were also significantly up-regulated in polyp-free colon mucosa. Similar changes occurred in morphologically normal mucosa of surgical sections taken from human cancer patients, frequently extending to the margins. Thus, morphologically normal colon mucosa in APC min mice and in human cancer patients is not metabolically normal. Altered gene expression in this tissue does not appear to result from a field effect because there was no correlation between extent of altered regulation and distance from polyp or tumor. Our data suggest that alterations of expression levels of these genes may be an early event in carcinogenesis and a marker of risk for the development of colon cancer.

Rotator cuff tears represent the most common shoulder injuries in the United States. The debilitating effect of this degenerative condition coupled with the high incidence of failure associated with existing graft choices underscore the clinical need for alternative grafting solutions. The two critical design criteria for the ideal tendon graft would require the graft to not only exhibit physiologically relevant mechanical properties but also be able to facilitate functional graft integration by promoting the regeneration of the native tendon-to-bone interface. Centered on these design goals, this review will highlight current approaches to functional and integrative tendon repair. In particular, the application of biomimetic design principles through the use of nanofiber- and nanocomposite-based scaffolds for tendon tissue engineering will be discussed. This review will begin with nanofiber-based approaches to functional tendon repair, followed by a section highlighting the exciting research on tendon-to-bone interface regeneration, with an emphasis on implementation of strategic biomimicry in nanofiber scaffold design and the concomitant formation of graded multi-tissue systems for integrative soft tissue repair. This review will conclude with a summary and future directions section.