BCL-3 promotes a cancer stem cell phenotype by enhancing β-catenin signalling in colorectal tumour cells.

To decrease bowel cancer incidence and improve survival, we need to understand the mechanisms that drive tumorigenesis. Recently, B-cell lymphoma 3 (BCL-3; a key regulator of NF-κB signalling) has been recognised as an important oncogenic player in solid tumours. Although reported to be overexpressed in a subset of colorectal cancers (CRCs), the role of BCL-3 expression in colorectal tumorigenesis remains poorly understood.

Identification of Mutation as a Genetic Driver of Prostate Cancer That Cooperates with Loss to Accelerate Progression and Castration-Resistant Growth.

Genetic alterations that potentiate PI3K signaling are frequent in prostate cancer, yet how different genetic drivers of the PI3K cascade contribute to prostate cancer is unclear. Here, we report mutation/amplification correlates with poor survival of patients with prostate cancer. To interrogate the requirement of different PI3K genetic drivers in prostate cancer, we employed a genetic approach to mutate in mouse prostate epithelium.

Synergistic targeting of breast cancer stem-like cells by human γδ T cells and CD8 T cells.

The inherent resistance of cancer stem cells (CSCs) to existing therapies has largely hampered the development of effective treatments for advanced malignancy. To help develop novel immunotherapy approaches that efficiently target CSCs, an experimental model allowing reliable distinction of CSCs and non-CSCs was set up to study their interaction with non-MHC-restricted γδ T cells and antigen-specific CD8 T cells. Stable lines with characteristics of breast CSC-like cells were generated from ras-transformed human mammary epithelial (HMLER) cells as confirmed by their CD44 CD24 GD2 phenotype, their mesenchymal morphology in culture and their capacity to form mammospheres under non-adherent conditions, as well as their potent tumorigenicity, self-renewal and differentiation in xenografted mice.

Developmental programming mediated by complementary roles of imprinted Grb10 in mother and pup.

Developmental programming links growth in early life with health status in adulthood. Although environmental factors such as maternal diet can influence the growth and adult health status of offspring, the genetic influences on this process are poorly understood. Using the mouse as a model, we identify the imprinted gene Grb10 as a mediator of nutrient supply and demand in the postnatal period.

Bcl3 selectively promotes metastasis of ERBB2-driven mammary tumors.

Bcl3 is a putative proto-oncogene deregulated in hematopoietic and solid tumors. Studies in cell lines suggest that its oncogenic effects are mediated through the induction of proliferation and inhibition of cell death, yet its role in endogenous solid tumors has not been established. Here, we address the oncogenic effect of Bcl3 in vivo and describe how this Stat3-responsive oncogene promotes metastasis of ErbB2-positive mammary tumors without affecting primary tumor growth or normal mammary function.

Evaluation of a fluorescent derivative of AMD3100 and its interaction with the CXCR4 chemokine receptor.

AMD3100 is a potent and selective antagonist of the CXCR4 receptor; it has been shown to block the route of entry of HIV into host T-cells. This compound and its analogues have since been found to act as haematopoietic stem cell mobilisation agents and, more recently, as anti-cancer agents. Here, we have examined a fluorescent derivative of AMD3100, L(1), which offered the potential to assess the behaviour of AMD3100 at the cell surface by using optical imaging modalities.

Suppression of apoptosis inhibitor c-FLIP selectively eliminates breast cancer stem cell activity in response to the anti-cancer agent, TRAIL.

Introduction: It is postulated that breast cancer stem cells (bCSCs) mediate disease recurrence and drive formation of distant metastases - the principal cause of mortality in breast cancer patients. Therapeutic targeting of bCSCs, however, is hampered by their heterogeneity and resistance to existing therapeutics. In order to identify strategies to selectively remove bCSCs from breast cancers, irrespective of their clinical subtype, we sought an apoptosis mechanism that would target bCSCs yet would not kill normal cells.

Stat3 controls lysosomal-mediated cell death in vivo.

It is well established that lysosomes play an active role during the execution of cell death. A range of stimuli can lead to lysosomal membrane permeabilization (LMP), thus inducing programmed cell death without involvement of the classical apoptotic programme. However, these lysosomal pathways of cell death have mostly been described in vitro or under pathological conditions.

A dual role for oncostatin M signaling in the differentiation and death of mammary epithelial cells in vivo.

Recent studies in breast cancer cell lines have shown that oncostatin M (OSM) not only inhibits proliferation but also promotes cell detachment and enhances cell motility. In this study, we have looked at the role of OSM signaling in nontransformed mouse mammary epithelial cells in vitro using the KIM-2 mammary epithelial cell line and in vivo using OSM receptor (OSMR)-deficient mice. OSM and its receptor were up-regulated approximately 2 d after the onset of postlactational mammary regression, in response to leukemia inhibitory factor (LIF)-induced signal transducer and activator of transcription-3 (STAT3).

The genes induced by signal transducer and activators of transcription (STAT)3 and STAT5 in mammary epithelial cells define the roles of these STATs in mammary development.

Prolactin and leukemia inhibitory factor (LIF) have different roles in the adult mammary gland, which are mediated in part by the signal transducers and activators of transcription (STAT)5 and STAT3. In vivo studies have shown that STAT5 contributes to prolactin-dependent lobuloalveolar development and lactation whereas STAT3 mediates LIF-dependent epithelial apoptosis during postlactational involution. To understand the molecular basis of these STAT-dependent pathways, we demonstrate the ligand-independent effects of STAT5 and STAT3 in mammary epithelial cells in vitro and also identify the genes regulated by these related transcription factors.

Regulation of genes encoding proteolytic enzymes during mammary gland development.

The mammary gland undergoes extensive tissue remodelling during each lactation cycle. During pregnancy, the epithelial compartment of the gland is vastly expanded (Benaud et al. 1998).

Stat3-induced apoptosis requires a molecular switch in PI(3)K subunit composition.

Physiological apoptosis is induced by a switch from survival to death signalling. Dysregulation of this process is frequently associated with cancer. A powerful model for this apoptotic switch is mammary gland involution, during which redundant milk-producing epithelial cells undergo apoptosis.

Gene expression profiling of mammary gland development reveals putative roles for death receptors and immune mediators in post-lactational regression.

Introduction: In order to gain a better understanding of the molecular processes that underlie apoptosis and tissue regression in mammary gland, we undertook a large-scale analysis of transcriptional changes during the mouse mammary pregnancy cycle, with emphasis on the transition from lactation to involution.

Method: Affymetrix microarrays, representing 8618 genes, were used to compare mammary tissue from 12 time points (one virgin, three gestation, three lactation and five involution stages). Six animals were used for each time point.

Microarray analysis of the involution switch.

Mammary epithelial cells (MEC) undergo a series of developmental decisions during a pregnancy cycle. The switches from proliferation to differentiation to secretion and then to cell death are precisely controlled. In order to identify critical changes associated with the transition from a secretory phenotype during lactation to dedifferentiation and cell death, we have undertaken a microarray analysis of mouse mammary gland development.

A dual, non-redundant, role for LIF as a regulator of development and STAT3-mediated cell death in mammary gland.

STAT3 is the key mediator of apoptosis in mammary gland. We demonstrate here that LIF is the physiological activator of STAT3, because in involuting mammary glands of Lif(-/-) mice, pSTAT3 is absent and the STAT3 target, C/EBPdelta, is not upregulated. Similar to Stat3 knockouts, Lif(-/-) mammary glands exhibit delayed involution, reduced apoptosis and elevated levels of p53.

Gene structure of the human metabotropic glutamate receptor 5 and functional analysis of its multiple promoters in neuroblastoma and astroglioma cells.

The metabotropic glutamate receptor 5 (mGluR5) has a discrete tissue expression mainly limited to neural cells. Expression of mGluR5 is developmentally regulated and undergoes dramatic changes in association with neuropathological disorders. We report the complete genomic structure of the mGluR5 gene, which is composed of 11 exons and encompasses approximately 563 kbp.