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New Philadelphia, PA, United States

Choi H.J.,University of Kansas Medical Center | Lui A.,University of Kansas Medical Center | Ogony J.,University of Kansas Medical Center | Jan R.,Research Institute of Fox Chase Cancer Center | And 2 more authors.
Breast Cancer Research

Introduction: Estrogen deprivation using aromatase inhibitors (AIs) is currently the standard of care for postmenopausal women with hormone receptor-positive breast cancer. Unfortunately, the majority of patients treated with AIs eventually develop resistance, inevitably resulting in patient relapse and, ultimately, death. The mechanism by which resistance occurs is still not completely known, however, recent studies suggest that impaired/defective interferon signaling might play a role. In the present study, we assessed the functional role of IFITM1 and PLSCR1; two well-known interferon response genes in AI resistance. Methods: Real-time PCR and Western blot analyses were used to assess mRNA and protein levels of IFITM1, PLSCR1, STAT1, STAT2, and IRF-7 in AI-resistant MCF-7:5C breast cancer cells and AI-sensitive MCF-7 and T47D cells. Immunohistochemistry (IHC) staining was performed on tissue microarrays consisting of normal breast tissues, primary breast tumors, and AI-resistant recurrence tumors. Enzyme-linked immunosorbent assay was used to quantitate intracellular IFNaα level. Neutralizing antibody was used to block type 1 interferon receptor IFNAR1 signaling. Small interference RNA (siRNA) was used to knockdown IFITM1, PLSCR1, STAT1, STAT2, IRF-7, and IFNaα expression. Results: We found that IFITM1 and PLSCR1 were constitutively overexpressed in AI-resistant MCF-7:5C breast cancer cells and AI-resistant tumors and that siRNA knockdown of IFITM1 significantly inhibited the ability of the resistant cells to proliferate, migrate, and invade. Interestingly, suppression of IFITM1 significantly enhanced estradiol-induced cell death in AI-resistant MCF-7:5C cells and markedly increased expression of p21, Bax, and Noxa in these cells. Significantly elevated level of IFNaα was detected in AI-resistant MCF-7:5C cells compared to parental MCF-7 cells and suppression of IFNaα dramatically reduced IFITM1, PLSCR1, p-STAT1, and p-STAT2 expression in the resistant cells. Lastly, neutralizing antibody against IFNAR1/2 and knockdown of STAT1/STAT2 completely suppressed IFITM1, PLSCR1, p-STAT1, and p-STAT2 expression in the resistant cells, thus confirming the involvement of the canonical IFNaα signaling pathway in driving the overexpression of IFITM1 and other interferon-stimulated genes (ISGs) in the resistant cells. Conclusion: Overall, these results demonstrate that constitutive overexpression of ISGs enhances the progression of AI-resistant breast cancer and that suppression of IFITM1 and other ISGs sensitizes AI-resistant cells to estrogen-induced cell death. © 2015 Choi et al.; licensee BioMed Central. Source

Saez B.,Harvard University | Saez B.,Massachusetts General Hospital | Saez B.,Harvard Stem Cell Institute | Ferraro F.,Harvard University | And 41 more authors.

The glycosyltransferase gene, Ext1, is essential for heparan sulfate production. Induced deletion of Ext1 selectively in Mx1-expressing bone marrow (BM) stromal cells, a known population of skeletal stem/progenitor cells, in adult mice resulted in marked changes inhematopoieticstemandprogenitorcell(HSPC)localization. HSPCegressedfromBMto spleen after Ext1 deletion. This was associated with altered signaling in the stromal cells and with reduced vascular cell adhesion molecule 1 production by them. Further, pharmacologic inhibition of heparan sulfate mobilized qualitatively more potent and quantitatively more HSPC from the BM than granulocyte colony-stimulating factor alone, including in a setting of granulocyte colony-stimulating factor resistance. The reduced presence of endogenous HSPC after Ext1 deletion was associated with engraftment of transfused HSPC without any toxic conditioning of the host. Therefore, inhibiting heparan sulfate production may provide a means for avoiding the toxicities of radiation or chemotherapy in HSPC transplantation for nonmalignant conditions. (Blood. 2014;124(19):2937-2947) © 2014 by The American Society of Hematology. Source

Sykes S.M.,Research Institute of Fox Chase Cancer Center | Scadden D.T.,Harvard Stem Cell Institute
Seminars in Hematology

Hematopoietic stem cells (HSCs) have the immense task of supplying an organism with enough blood to sustain a lifespan. Much of what is known about how this scant population of cells can meet the varying demand of producing more than 1011 cells per day comes from studies conducted in an animal that is a fraction of our size and lives roughly 1/30th of our lifespan. The differences in longevity can be expected to impose different demands on a cell essential for existence. It is therefore unsurprising that while the mouse has proven invaluable in defining the organizing principals of how hematopoiesis is governed, mediators of cell localization as well as a range of experimental methods, the differences in cell cycling, DNA repair and specific molecular features of HSCs in humans are evident and important. Here, the utility and drawbacks of the mouse as an experimental model for human HSC biology are discussed. © 2013 Elsevier Inc. Source

Di Marcantonio D.,University of Parma | Di Marcantonio D.,Research Institute of Fox Chase Cancer Center | Galli D.,University of Parma | Carubbi C.,University of Parma | And 11 more authors.
Experimental Cell Research

Introduction: Satellite cells are muscle resident stem cells and are responsible for muscle regeneration. In this study we investigate the involvement of PKCε during muscle stem cell differentiation in vitro and in vivo. Here, we describe the identification of a previously unrecognized role for the PKCε-HMGA1 signaling axis in myoblast differentiation and regeneration processes. Methods: PKCε expression was modulated in the C2C12 cell line and primary murine satellite cells in vitro, as well as in an in vivo model of muscle regeneration. Immunohistochemistry and immunofluorescence, RT-PCR and shRNA silencing techniques were used to determine the role of PKCε and HMGA1 in myogenic differentiation. Results: PKCε expression increases and subsequently re-localizes to the nucleus during skeletal muscle cell differentiation. In the nucleus, PKCε blocks Hmga1 expression to promote Myogenin and Mrf4 accumulation and myoblast formation. Following in vivo muscle injury, PKCε accumulates in regenerating, centrally-nucleated myofibers. Pharmacological inhibition of PKCε impairs the expression of two crucial markers of muscle differentiation, namely MyoD and Myogenin, during injury induced muscle regeneration. Conclusion: This work identifies the PKCε-HMGA1 signaling axis as a positive regulator of skeletal muscle differentiation. © 2015 Elsevier Inc. Source

Lev A.,Research Institute of Fox Chase Cancer Center | Sigal L.,Research Institute of Fox Chase Cancer Center
Cell Host and Microbe

How immune cells collaborate to clear a virus from the skin is not well understood. In this issue of Cell Host & Microbe, Hickman et al. (2013) show that spatially segregated Ly6G+ monocytes and CD8+ T cells act synergistically to clear vaccinia virus from a primary skin infection. © 2013 Elsevier Inc. Source

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