Breast Tumor Metastasis and Its Microenvironment: It Takes Both Seed and Soil to Grow a Tumor and Target It for Treatment.

Metastasis remains a major challenge in treating breast cancer. Breast tumors metastasize to organ-specific locations such as the brain, lungs, and bone, but why some organs are favored over others remains unclear. Breast tumors also show heterogeneity, plasticity, and distinct microenvironments.

Rhenium(I)-tricarbonyl complexes with methimazole and its selenium analogue: Syntheses, characterization and cell toxicity.

This study explores the effect of a thione/selone ligand on the cell toxicity (in vitro) and light activity of diimine Re(CO) complexes. Six rhenium(I) complexes with general formula fac-[Re(CO)(N,N')X] were prepared, where X = 2-mercapto-1-methylimidazole (methimazole; MMI), and 1-methylimidazole-2-selone (MSeI); N,N' = 2,2'-bipyridine (bpy), 1,10-phenanthroline (phen) and 2,9-dimethyl-1,10-phenanthroline (dmphen). Their triflate salts were characterized using single-crystal X-ray diffraction, H, C and 2D NMR, UV-vis and vibrational spectroscopy.

Stabilized COre gene and Pathway Election uncovers pan-cancer shared pathways and a cancer-specific driver.

Approaches systematically characterizing interactions via transcriptomic data usually follow two systems: (i) coexpression network analyses focusing on correlations between genes and (ii) linear regressions (usually regularized) to select multiple genes jointly. Both suffer from the problem of stability: A slight change of parameterization or dataset could lead to marked alterations of outcomes. Here, we propose Stabilized COre gene and Pathway Election (SCOPE), a tool integrating bootstrapped least absolute shrinkage and selection operator and coexpression analysis, leading to robust outcomes insensitive to variations in data.

The effect of sodium thiosulfate on cytotoxicity of a diimine Re(I) tricarbonyl complex.

Recently, diimine Re(i) tricarbonyl complexes have attracted great interest due to their promising cytotoxic effects. Here, we compare the cytotoxicity and cellular uptake of two Re(i) compounds fac-[(Re(CO)3(bpy)(H2O)](CF3SO3) (1) and Na(fac-[(Re(CO)3(bpy)(S2O3)])·H2O (bpy = 2,2'-bipyridine) (2). The Re-thiosulfate complex in 2 was characterized in two solvated crystal structures {Na(fac-[Re(CO)3(bpy)(S2O3)])·1.

Prolactin: A hormone with diverse functions from mammary gland development to cancer metastasis.

Prolactin has a rich mechanistic set of actions and signaling in order to elicit developmental effects in mammals. Historically, prolactin has been appreciated as an endocrine peptide hormone that is responsible for final, functional mammary gland development and lactation. Multiple signaling pathways impacted upon by the microenvironment contribute to cell function and differentiation.

Cytotoxicity, cellular localization and photophysical properties of Re(I) tricarbonyl complexes bound to cysteine and its derivatives.

The potential chemotherapeutic properties coupled to photochemical transitions make the family of fac-[Re(CO)(N,N)X] (N,N = a bidentate diimine such as 2,2'-bipyridine (bpy); X = halide, HO, pyridine derivatives, PR, etc.) complexes of special interest. We have investigated reactions of the aqua complex fac-[Re(CO)(bpy)(HO)](CFSO) (1) with potential anticancer activity with the amino acid L-cysteine (HCys), and its derivative N-acetyl-L-cysteine (HNAC), as well as the tripeptide glutathione (HA), under physiological conditions (pH 7.

Nuclear localization of dirhodium(ii) complexes in breast cancer cells by X-ray fluorescence microscopy.

The cellular distribution of three dirhodium(ii) complexes with a paddlewheel structure was investigated using synchrotron-based X-ray fluorescence microscopy and cell viability studies. Complexes with vacant axial sites displayed cytotoxic activity and nuclear accumulation whereas complexes in which the axial positions were blocked showed little to no toxicity nor uptake.

ATM Is Required for the Prolactin-Induced HSP90-Mediated Increase in Cellular Viability and Clonogenic Growth After DNA Damage.

Prolactin (PRL) acts as a survival factor for breast cancer cells, but the PRL signaling pathway and the mechanism are unknown. Previously, we identified the master chaperone, heat shock protein 90 (HSP90) α, as a prolactin-Janus kinase 2 (JAK2)-signal transducer and activator of transcription 5 (STAT5) target gene involved in survival, and here we investigated the role of HSP90 in the mechanism of PRL-induced viability in response to DNA damage. The ataxia-telangiectasia mutated kinase (ATM) protein plays a critical role in the cellular response to double-strand DNA damage.

What Is Breast in the Bone?

The normal developmental program that prolactin generates in the mammary gland is usurped in the cancerous process and can be used out of its normal cellular context at a site of secondary metastasis. Prolactin is a pleiotropic peptide hormone and cytokine that is secreted from the pituitary gland, as well as from normal and cancerous breast cells. Experimental and epidemiologic data suggest that prolactin is associated with mammary gland development, and also the increased risk of breast tumors and metastatic disease in postmenopausal women.

Prolactin receptor in breast cancer: marker for metastatic risk.

Prolactin and prolactin receptor signaling and function are complex in nature and intricate in function. Basic, pre-clinical and translational research has opened up our eyes to the understanding that prolactin and prolactin receptor signaling function differently within different cellular contexts and microenvironmental conditions. Its multiple roles in normal physiology are subverted in cancer initiation and progression, and gradually we are teasing out the intricacies of function and therapeutic value.

The Breast Cancer to Bone (B2B) Metastases Research Program: a multi-disciplinary investigation of bone metastases from breast cancer.

Background: Bone is the most common site of breast cancer distant metastasis, affecting 50-70 % of patients who develop metastatic disease. Despite decades of informative research, the effective prevention, prediction and treatment of these lesions remains elusive. The Breast Cancer to Bone (B2B) Metastases Research Program consists of a prospective cohort of incident breast cancer patients and four sub-projects that are investigating priority areas in breast cancer bone metastases.

The Role of Prolactin in Bone Metastasis and Breast Cancer Cell-Mediated Osteoclast Differentiation.

Background: Metastasis to the bone is a deleterious aspect of breast cancer and is a preferred site that results in bone loss. Hormones such as prolactin (PRL) have not yet been studied for their role in modulating the secondary tumor bone microenvironment.

Methods: We used quantitative immunohistochemistry with 134 samples of human primary breast cancer and 17 matched primary breast cancers and bone metastases.

The bone morphogenetic protein receptor-1A pathway is required for lactogenic differentiation of mammary epithelial cells in vitro.

Bone morphogenetic proteins (BMPs) have been implicated in the control of proliferation, tissue formation, and differentiation. BMPs regulate the biology of stem and progenitor cells and can promote cellular differentiation, depending on the cell type and context. Although the BMP pathway is known to be involved in early embryonic development of the mammary gland via mesenchymal cells, its role in later epithelial cellular differentiation has not been examined.

Characterization of mammary epithelial cell line HC11 using the NIA 15k gene array reveals potential regulators of the undifferentiated and differentiated phenotypes.

Differentiation of undifferentiated mammary epithelial stem and/or progenitor cells results in the production of luminal-ductal and myoepithelial cells in the young animal and upon pregnancy, the production of luminal alveolar cells. A few key regulators of differentiation have been identified, though it is not known yet how these proteins function together to achieve their well-orchestrated products. In an effort to identify regulators of early differentiation, we screened the NIA 15k gene array of 15,247 developmentally expressed genes using mouse mammary epithelial HC11 cells as a model of differentiation.

Heat shock protein-90-alpha, a prolactin-STAT5 target gene identified in breast cancer cells, is involved in apoptosis regulation.

Introduction: The prolactin-Janus-kinase-2-signal transducer and activator of transcription-5 (JAK2-STAT5) pathway is essential for the development and functional differentiation of the mammary gland. The pathway also has important roles in mammary tumourigenesis. Prolactin regulated target genes are not yet well defined in tumour cells, and we undertook, to the best of our knowledge, the first large genetic screen of breast cancer cells treated with or without exogenous prolactin.

Mammary epithelial stem and progenitor cells and the prolactin pathway.

Prolactin is a pleiotropic peptide hormone and cytokine that is secreted from the pituitary gland and locally within various tissues of the body for autocrine and paracrine signal transduction. It controls proliferation and differentiation in a number of body tissues and increasing evidence indicates that it controls these functions in undifferentiated stem and progenitor cells of adult tissues, such as mesenchymal stem cells, hematopoietic progenitors, neural stem cells, oligodendrocyte precursor cells and possibly in mammary gland stem/progenitor cells. These roles in these undifferentiated cell types also implicate prolactin in the stem cell theory of cancer, supporting its known roles in cancer formation and progression.

A sparing procedure to clear the mouse mammary fat pad of epithelial components for transplantation analysis.

Transplantation of epithelial cells into cleared fat pads is a widely used technique in the study of mammary gland biology. It was first described in 1959 and has remained a valuable technique, most recently in conjunction with the analysis of mammary anlagen from knockout mice with an embryonic lethal phenotype or reproductive defect, and for mammary epithelial stem-cell assays or analysis of precancerous cells. Mammary glands, unlike most other organs, mainly develop postnatally.

Epidermolysis bullosa simplex in Scotland caused by a spectrum of keratin mutations.

Epidermolysis bullosa simplex (EBS) is an inherited skin disorder caused by mutations in keratins K5 (keratin 5) and K14 (keratin 14), with fragility of basal keratinocytes leading to epidermal cytolysis and blistering. Patients present with widely varying severity and are classified in three main subtypes: EBS Weber-Cockayne (EBS-WC), EBS Köbner (EBS-K), and EBS Dowling-Meara (EBS-DM), based on distribution and pattern of blisters. We could identify K5/K14 mutations in 20 out of the 43 families registered as affected by dominant EBS in Scotland; with previous studies this covers 70% of all Scottish EBS patients, making this the most comprehensively analyzed EBS population.

Generation and characterization of epidermolysis bullosa simplex cell lines: scratch assays show faster migration with disruptive keratin mutations.

Background: Epidermolysis bullosa simplex (EBS) is an inherited skin fragility disorder caused by mutations in keratin intermediate filament proteins. While discoveries of these mutations have increased understanding of the role of keratins and other intermediate filaments in epithelial tissues, progress towards the development of therapy for these disorders is much slower.

Objectives: Cell culture model systems that display these structural defects are needed for analysis of the cellular consequences of the mutations and to enable possible therapeutic strategies to be developed.

Comparative proteomic analysis of proliferating and functionally differentiated mammary epithelial cells.

Proliferation and differentiation of mammary epithelial cells are governed by hormonal stimuli, cell-cell, and cell-matrix interactions. Terminal differentiation of mammary epithelial cells depends upon the action of the lactogenic hormones, insulin, glucocorticoids, and prolactin that enable them to synthesize and secrete milk proteins. These differentiated cells are polarized and carry out vectorial transport of milk constituents across the apical plasma membrane.

DNA based prenatal testing for the skin blistering disorder epidermolysis bullosa simplex.

Epidermolysis bullosa simplex (EBS) is a skin fragility disorder in which mild physical trauma leads to blistering. The phenotype of the disorder is variable, from relatively mild affecting only the hands and/or feet, to very severe with widespread blistering. For the severest forms of EBS there is a demand for prenatal diagnosis which until now has involved a fetal skin biopsy in the second trimester.

Laryngeal involvement in the Dowling-Meara variant of epidermolysis bullosa simplex with keratin mutations of severely disruptive potential.

The clinical features of the Dowling-Meara variant of epidermolysis bullosa simplex (EBS-DM) can, in an infant, be indistinguishable from other severe forms of epidermolysis bullosa (EB). Two unrelated infants with no family history of skin disease are described who, within hours of birth, developed extensive blistering of skin and oral mucosae and who both subsequently developed hoarse cries. Despite this superficial resemblance to other forms of EB, electron microscopy revealed a basal cell rupture and keratin aggregates characteristic of EBS-DM in the skin of both infants and in the vocal cord epithelium of one.

Severe palmo-plantar hyperkeratosis in Dowling-Meara epidermolysis bullosa simplex caused by a mutation in the keratin 14 gene (KRT14).

Mutant keratins 5 or 14 are implicated in the etiology of epidermolysis bullosa simplex (EBS). The catalog of mutations has established certain patterns of mutation clusters from which it may be possible, along with associated biochemical data, to predict phenotypic severity. It is becoming apparent that some of these assumptions may now require modification.