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Introduction
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May 2005 - August 2008
Publications
Publications (34)
Background
Sirtuin 6 (SIRT6) is a NAD ⁺ -dependent deacetylase with key roles in cell metabolism. High SIRT6 expression is associated with adverse prognosis in breast cancer (BC) patients. However, the mechanisms through which SIRT6 exerts its pro-oncogenic effects in BC remain unclear. Here, we sought to define the role of SIRT6 in BC cell metabol...
Arginine metabolism plays a significant role in regulating cell function, affecting tumor growth and metastatization. To study the effect of the arginine-catabolizing enzyme arginase 1 (ARG1) on tumor microenvironment, we generated a mouse model of mammary carcinogenesis by crossbreeding a transgenic mouse line overexpressing ARG1 in macrophages (F...
Nicotinamide phosphoribosyltransferase (NAMPT) is the rate‐limiting enzyme in the NAD⁺ salvage pathway from nicotinamide. By controlling the biosynthesis of NAD⁺, NAMPT regulates the activity of NAD⁺‐converting enzymes, such as CD38, poly‐ADP‐ribose polymerases, and sirtuins (SIRTs). SIRT6 is involved in the regulation of a wide number of metabolic...
Studies show that the NAD+ dependent histone deacetylase Sirt6 exerts tumor suppressive effects in different tissues and organs by mechanisms that include the dampening of the Warburg effect and of Myc activity. In breast cancer (BC), Sirt6 was recently shown to blunt PI3K signaling and to reduce cancer stem cell like capacity in tumors with mutate...
The NAD(+)-dependent deacetylase SIRT6 is an emerging cancer drug target, whose inhibition sensitizes cancer cells to chemo-radiotherapy and has pro-differentiating effects. Here we report on the identification of novel SIRT6 inhibitors with a salicylate-based structure. The new SIRT6 inhibitors show improved potency and specificity compared to the...
Sirtuin 6 (SIRT6) is a sirtuin family member involved in a wide range of physiologic and disease processes, including cancer and glucose homeostasis. Based on the roles played by SIRT6 in different organs, including its ability to repress the expression of glucose transporters and glycolytic enzymes, inhibiting SIRT6 has been proposed as an approac...
Mechanisms for the progression of ductal carcinoma in situ (DCIS) to invasive breast carcinoma remain unclear. Previously we showed that the transition to invasiveness in the mammary intraepithelial neoplastic outgrowth (MINO) model of DCIS does not correlate with its serial acquisition of genetic mutations. We hypothesized instead that progression...
Linear regression followed by analysis of covariance (ANCOVA) for the representative data of the pHi during the recovery phase (1400–1800 s) of the ammonium washout experiment in nMEC, Met1, and PyVmT cells showed that the slope of the best-fit lines for both cancer cell types (Met1 and PyVm) were significantly different (P < 0.001) compared with t...
Cartoon explaining how the NH4Cl washout protocol is used to measure pHi regulation after acidification. When NH4Cl is added to the superfusate, the concentrations of NH3 in the intra- and extracellular fluids are assumed to be equivalent and, according to the isohydric principle, fixed intracellular buffers are considered to be in equilibrium with...
Met1 cancer cells have a higher rate of intracellular acidification than nMEC cells during sodium washout experiments where proton extrusion is blocked by NHE1 inhibition. Linear regression analysis for nMEC and Met1 individual pHi values followed by analysis of covariance (ANCOVA) showed significant difference (P < 0.001), between the slopes of th...
Dendritic cells (DCs) are antigen-presenting cells that critically influence decisions about immune activation or tolerance. Impaired DC function is at the core of common chronic disorders and contributes to reduce immunocompetence during aging. Knowledge on the mechanisms regulating DC generation and function is necessary to understand the immune...
Arginase (ARG) is a metabolic enzyme present in two isoforms that hydrolyze l-arginine to urea and ornithine. In humans, ARG isoform 1 is also expressed in cells of the myeloid lineage. ARG activity
promotes tumour growth and inhibits T lymphocyte activation. However, the two ARG transgenic mouse lines produced so far failed
to show such effects. W...
The NAD(+)-dependent sirtuin SIRT6 is highly expressed in human breast, prostate, and skin cancer where it mediates resistance to cytotoxic agents and prevents differentiation. Thus, SIRT6 is an attractive target for the development of new anticancer agents to be used alone or in combination with chemo- or radiotherapy. Here we report on the identi...
Tyrosine kinase inhibitors (TKIs) are now the mainstay of treatment in many types of cancer. However, their benefit is frequently short-lived, mandating the search for safe potentiation strategies. Cycles of fasting enhance the activity of chemo-radiotherapy in preclinical cancer models and dietary approaches based on fasting are currently explored...
Boosting NAD+ biosynthesis with NAD+ intermediates has been proposed as a strategy for preventing and treating age-associated diseases, including cancer. However, concerns in this area were raised by observations that nicotinamide phosphoribosyltransferase (NAMPT), a key enzyme in mammalian NAD+ biosynthesis, is frequently up-regulated in human mal...
SIRT6 is an NAD+-dependent deacetylase with a role in the transcriptional control of metabolism and aging, but also in genome stability and inflammation. Broad therapeutic applications are foreseen for SIRT6 inhibitors, including uses in diabetes, immune-mediated disorders, and cancer. Here, we report on the identification of the first selective SI...
Decidual Natural Killer cells accumulate at the fetal-maternal interface and play a key role for a successful pregnancy. However, their origin is still unknown. Do they derive from peripheral Natural Killer cells recruited in decidua or represent a distinct population that origins in situ? Here we identified Natural Killer precursors in decidua and...
NAD+ biosynthesis through nicotinamide phosphoribosyltransferase (NAMPT) holds potential as a target for the treatment of inflammatory disorders due to NAD+'s role in immune cell signaling and metabolism. In addition to its activity as an enzyme, NAMPT is also secreted in the extracellular space where it acts as a pro-inflammatory and pro-angiogeni...
1. Conjugated linoleic acid (CLA) contains conjugated double bonds and is known as a family of isomers of linoleic acid that can be found in the meat and dairy products.
2. In vitro studies have shown that CLA can inhibit the growth of mammary, colon, colorectal, gastric, prostate, and malignant liver cell lines and has also been shown to induce th...
Epithelial-mesenchymal transition tumorigenesis in the mouse has been described for over 100 years using various terms and with little comprehension of the underlying mechanisms. Recently, epithelial-mesenchymal transition tumors have been recognized in mammary glands of genetically engineered mice. This review provides a historical perspective and...
An Excel file showing a microsatellite analysis of MINO and matched tumor. Listed are all microsatellite PCR nucleotide length results. Open cells indicate failed or unreadable reactions.
A Word document outlining the CGH procedure.
A tif file summarizing CGH and microsatellite analysis by line. For each line, samples of MINO and the matched tumor were analyzed by BAC array CGH and multiplexed PCR for microsatellite changes. For CGH results, changes that were seen in all of the MINO or tumor samples from each line are depicted in solid color, and changes seen in less than 100%...
A tif file showing serial transplantation of MINOSphere-derived outgrowth. Histology (hematoxylin and eosin stained, formalin-fixed, paraffin-embedded 4 μm sections) of donor (A, D), second (B, E), and third (C, F) serial transplantations from the single cell MINOsphere derived outgrowths from MINO line D (panels A, B, and C) and MINO line 4 (panel...
The 'MINO' (mammary intraepithelial neoplasia outgrowth) mouse model of ductal carcinoma in situ (DCIS) consists of six lines with distinct morphologic phenotypes and behavior, each meeting experimentally defined criteria for 'precancer'. Specifically, these lines grow orthotopically in cleared mammary fat pads and consistently progress to an invas...
The term EMT (epithelial-mesenchymal transition) is used in many settings. This term is used to describe the mechanisms facilitating cellular repositioning and redeployment during embryonic development and tissue reconstruction after injury. Recently, EMT has also been applied to potential mechanisms for malignant progression and has appeared as a...
Rapamycin has been shown to have antitumor effects in various tumor models. To study the effect of rapamycin at different stages of breast cancer development, we used two unique mouse models of breast cancer with activated phosphatidylinositol 3-kinase (PI3K) pathway. Met-1 tumors are highly invasive and metastatic, and mammary intraepithelial neop...
Embryonal carcinoma (EC) cells, stem cells of teratocarcinoma, represent an excellent model to study the developmental mechanisms that, inappropriately reactivated, can drive tumorigenesis. EC cells are very aggressive, and grow rapidly when injected into adult syngeneic mice. However, when injected into blastocysts, they revert to normality, givin...
Newborn gene therapy, because it can prevent the damage caused by the onset of a disease, deserves specific attention. To evaluate gene transfer in tissues of newborn mice, we used a human immunodeficiency virus (HIV)-2 based lentiviral vector pseudotyped with vesicular stomatitis virus G glycoprotein expressing the green fluorescent protein report...
We previously demonstrated that expression of human FGF4 in the epithelial compartment of murine mammary glands caused hyperplasia during lactation and a dramatic delay in gland involution due to inhibition of cellular apoptosis. We now analyse the effects of transgene expression during development of the organ. Expression of WAP- Fgf4 initiate wit...
