No abstract

Cancer stem cells (CSCs) are tumor cells that possess the capacity to divide asymmetrically, producing one stem cell (self-renewal) and one progenitor cell that is able to generate heterogeneous lineages of the cancer cells that comprise tumors. CSCs in human breast tumors were initially identified in 2003 by Al-Hajj et al, 1 who discovered a cellular population characterized by the cell-surface markers CD44 ϩ /CD24 Ϫ/low /ESA ϩ and lack of expression of CD2, CD3, CD10, CD16, CD18, CD31, CD64, and CD140b (lineage Ϫ ). As few as 200 of these cells were able to form tumors when xenotransplanted into NOD/SCID mice, whereas tens of thousands of other cells could not.1 The tumors generated recapitulated the phenotypic heterogeneity of the parental tumor, containing a minority of CD44 ϩ /CD24 Ϫ/low /lineage Ϫ cells that can be serially passaged to form new tumors.1 The CD44 ϩ /CD24 Ϫ phenotype has been used extensively to identify and isolate breast cancer cells with increased tumorigenicity.Putative breast CSCs have also been isolated from patient samples after in vitro propagation and from breast cancer cell lines, through their ability to proliferate in suspension as nonadherent spheres (mammospheres). 1-4Because the capacity to form mammospheres is increased in early progenitor/stem cells, this system has been widely used as an indirect measurement of the number of cells with self-renewal capability. 5,6 In accord with in vivo data, mammospheres from breast cancer cells are enriched in cells with the CD44 ϩ /CD24 /CD24Ϫ retain self-renewal capability, other markers for human breast CSCs have been investigated. Activity of the aldehyde dehydrogenase (ALDH) family of cytosolic isoenzymes is inSupported in part by PASPA-UNAM (Programa de Apoyos para la Superación del Personal Académico-Universidad Nacional Autónoma de México) (M.A.V.-V.) and the NIH (grants R01CA070896, R01CA075503, R01CA107382, R01CA132115, and R01CA086072 to R.G.P. and R01CA120876 to M.P.L.). The Kimmel Cancer Center was supported by an NIH cancer center core grant (P30CA56036 to R.G.P.). This project is funded in part from the Marian C. Falk Medical Research Trust and a grant from the Pennsylvania Department of Health (R.G.P.).

No abstract

Epigenetic modifications play a key role in the patho-physiology of many tumors and the current use of agents targeting epigenetic changes has become a topic of intense interest in cancer research. DNA methyltransferase (DNMT) inhibitors represent a promising class of epigenetic modulators. Research performed yielded promising anti-tumorigenic activity for these agents in vitro and in vivo against a variety of hematologic and solid tumors. These epigenetic modulators cause cell cycle and growth arrest, differentiation and apoptosis. Rationale for combining these agents with cytotoxic therapy or radiation is straightforward since the use of DNMT inhibitor offers greatly improved access for cytotoxic agents or radiation for targeting DNA-protein complex. The positive results obtained with these combined approaches in preclinical cancer models demonstrate the potential impact DNMT inhibitors may have in treatments of different cancer types. Therefore, as the emerging interest in use of DNMT inhibitors as a potential chemo- or radiation sensitizers is constantly increasing, further clinical investigations are inevitable in order to finalize and confirm the consistency of current observations.The present article will provide a brief review of the biological significance and rationale for the clinical potential of DNMT inhibitors in combination with other chemotherapeutics or ionizing radiation. The molecular basis and mechanisms of action for these combined treatments will be discussed herein.

No abstract

The dachshund (dac) gene was initially described as a mutant phenotype in flies featuring extremely short legs relative to their body length. Functioning as a dominant suppressor of the ellipse mutation, a hypermorphic allele of the Epidermal Growth Factor Receptor (EGFR), the dac gene plays a key role in metazoan development, regulating ocular, limb, brain, and gonadal development. In the Drosophila eye, dac is a key component of the Retinal Determination Gene Network (RDGN) governing the normal initiation of the morphogenetic furrow and thereby eye development. Recent studies have demonstrated an important role for human DACHSHUND in tumorigenesis, in particular, breast, prostate and ovarian cancer. The molecular mechanisms by which DACH1 regulates differentiation and tumorigenesis are discussed herein. dachshund in Gonadal DevelopmentThe Retinal Determination Gene Network, RDGN, plays an important role in Drosophila gonadal development [1][2][3]. In Drosophila, the male and female genital tracts undergo patterning gene expression in homologous regions in both sexes. In this regard, wg is expressed along the anterior-posterior (AP) border, flanked by a broad stripe of dpp expression [4]. In contrast, dac is expressed in a sex-specific manner. dac function is important for development of both male and female genitalia. Male dac mutant flies have abnormal external male genital structures known as claspers, whereas female dac mutant flies have defective ovarian duct formation [4]. In the male genital disc, wg represses dac expression while dpp signaling induces it [4,5]. In contrast, wg activates dac expression while dpp represses dac expression in the female genital disc (Figure 1). The Eya protein also plays an important role in Drosophila gonad development [2,6]. eya is expressed in the somatic gonadal precursor and required for the maintenance of somatic gonadal precursor (SGP) cell fate. The function of dac as a part of the RDGN in sex determination in flies indicates the importance of this gene in development not only in Arthropods but also in mammalian models, as we will discuss later in this review. dac has also been shown to play a crucial role in Drosophila eye development (Box 1). *Corresponding Author: Richard G. Pestell, The Kimmel Cancer Center, Department of Cancer Biology, Thomas Jefferson University, 233 South 10 th Street, Philadelphia, PA 19107, Tel: 213-503-5692; Fax: 215-503-9334, For Reprints: Cecilia.Deemer@kimmelcancercenter.org. # Authors have contributed equally to the manuscript.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public...

The Drosophila Dachshund (Dac) gene, cloned as a dominant inhibitor of the hyperactive growth factor mutant ellipse, encodes a key component of the retinal determination gene network that governs cell fate. Herein, cyclic amplification and selection of targets identified a DACH1 DNA-binding sequence that resembles the FOX (Forkhead box-containing protein) binding site. Genome-wide in silico promoter analysis of DACH1 binding sites identified gene clusters populating cellular pathways associated with the cell cycle and growth factor signaling. ChIP coupled with high-throughput sequencing mapped DACH1 binding sites to corresponding gene clusters predicted in silico and identified as weight matrix resembling the cyclic amplification and selection of targets-defined sequence. DACH1 antagonized FOXM1 target gene expression, promoter occupancy in the context of local chromatin, and contactindependent growth. Attenuation of FOX function by the cell fate determination pathway has broad implications given the diverse role of FOX proteins in cellular biology and tumorigenesis.cell fate determination | Forkhead protein | transcription factor | tumor suppressor | dachshund homolog 1

The Dachshund (dac) gene, initially cloned as a dominant inhibitor of the Drosophila hyperactive EGFR mutant ellipse, encodes a key component of the cell fate determination pathway involved in Drosophila eye development. Analysis of more than 2,200 breast cancer samples showed improved survival by some 40 months in patients whose tumors expressed DACH1. Herein, DACH1 and estrogen receptor-α (ERα) expressions were inversely correlated in human breast cancer. DACH1 bound and inhibited ERα function. Nuclear DACH1 expression inhibited estradiol (E2)-induced DNA synthesis and cellular proliferation. DACH1 bound ERα in immunoprecipitation-Western blotting, associated with ERα in chromatin immunoprecipitation, and inhibited ERα transcriptional activity, requiring a conserved DS domain. Proteomic analysis identified proline, glutamic acid, and leucine rich protein 1 (PELP1) as a DACH1-binding protein. The DACH1 COOH terminus was required for binding to PELP1. DACH1 inhibited induction of ERα signaling. E2 recruited ERα and disengaged corepressors from DACH1 at an endogenous ER response element, allowing PELP1 to serve as an ERα coactivator. DACH1 expression, which is lost in poor prognosis human breast cancer, functions as an endogenous inhibitor of ERα function.