Evaluation of the Mammalian Aquaporin Inhibitors Auphen and Z433927330 in Treating Breast Cancer.

AQPs contribute to breast cancer progression and metastasis. We previously found that genetic inhibition of Aqp7 reduces primary tumor burden and metastasis in breast cancer. In this study, we utilized two AQP inhibitors, Auphen and Z433927330, to evaluate the efficacy of therapeutic inhibition of AQPs in breast cancer treatment.

Controlled mechanical loading affects the osteocyte transcriptome in porcine trabecular bone in situ.

Introduction: Osteocytes modulate bone adaptation in response to mechanical stimuli imparted by the deforming bone tissue in which they are encased by communicating with osteoclasts and osteoblasts as well as other osteocytes in the lacuna-canalicular network through secreted cytokines and chemokines. Understanding the transcriptional response of osteocytes to mechanical stimulation in situ could identify new targets to inhibit bone loss or enhance bone formation in the presence of diseases like osteoporosis or metastatic cancer. We compared the mechanically regulated transcriptional response of osteocytes in trabecular bone following one or three days of controlled mechanical loading.

Aquaporins: New players in breast cancer progression and treatment response.

Aquaporins (AQPs) are a family of small transmembrane proteins that selectively transport water and other small molecules and ions following an osmotic gradient across cell plasma membranes. This enables them to regulate numerous functions including water homeostasis, fat metabolism, proliferation, migration, and adhesion. Previous structural and functional studies highlight a strong biological relationship between AQP protein expression, localization, and key biological functions in normal and cancer tissues, where aberrant AQP expression correlates with tumorigenesis and metastasis.

The effect of marrow secretome and culture environment on the rate of metastatic breast cancer cell migration in two and three dimensions.

Metastasis is responsible for over 90% of cancer-related deaths, and bone is the most common site for breast cancer metastasis. Metastatic breast cancer cells home to trabecular bone, which contains hematopoietic and stromal lineage cells in the marrow. As such, it is crucial to understand whether bone or marrow cells enhance breast cancer cell migration toward the tissue.

In vivo evaluation of CD38 and CD138 as targets for nanoparticle-based drug delivery in multiple myeloma.

Background: Drug-loaded nanoparticles have established their benefits in the fight against multiple myeloma; however, ligand-targeted nanomedicine has yet to successfully translate to the clinic due to insufficient efficacies reported in preclinical studies.

Methods: In this study, liposomal nanoparticles targeting multiple myeloma via CD38 or CD138 receptors are prepared from pre-synthesized, purified constituents to ensure increased consistency over standard synthetic methods. These nanoparticles are then tested both in vitro for uptake to cancer cells and in vivo for accumulation at the tumor site and uptake to tumor cells.

Stiff stroma increases breast cancer risk by inducing the oncogene ZNF217.

Women with dense breasts have an increased lifetime risk of malignancy that has been attributed to a higher epithelial density. Quantitative proteomics, collagen analysis, and mechanical measurements in normal tissue revealed that stroma in the high-density breast contains more oriented, fibrillar collagen that is stiffer and correlates with higher epithelial cell density. microRNA (miR) profiling of breast tissue identified miR-203 as a matrix stiffness-repressed transcript that is downregulated by collagen density and reduced in the breast epithelium of women with high mammographic density.

Aquaporin-7 Regulates the Response to Cellular Stress in Breast Cancer.

The complex yet interrelated connections between cancer metabolism, gene expression, and oncogenic driver genes have the potential to identify novel biomarkers and drug targets with prognostic and therapeutic value. Here we effectively integrated metabolomics and gene expression data from breast cancer mouse models through a novel unbiased correlation-based network analysis. This approach identified 35 metabolite and 34 gene hubs with the most network correlations.

Engineering peptide-targeted liposomal nanoparticles optimized for improved selectivity for HER2-positive breast cancer cells to achieve enhanced in vivo efficacy.

Here, we report rationally engineered peptide-targeted liposomal doxorubicin nanoparticles that have an enhanced selectivity for HER2-positive breast tumor cells with high purity, reproducibility, and precision in controlling stoichiometry of targeting peptides. To increase HER2-positive tumor cell selective drug delivery, we optimized the two most important design parameters, peptide density and linker length, via systematic evaluations of their effects on both in vitro cellular uptake and in vivo tumor accumulation and cellular uptake. The optimally designed nanoparticles were finally evaluated for their tumor inhibition efficacy using in vivo MMTV-neu transplantation mouse model.

A Statistical Approach of Background Removal and Spectrum Identification for SERS Data.

SERS (surface-enhanced Raman scattering) enhances the Raman signals, but the plasmonic effects are sensitive to the chemical environment and the coupling between nanoparticles, resulting in large and variable backgrounds, which make signal matching and analyte identification highly challenging. Removing background is essential, but existing methods either cannot fit the strong fluctuation of the SERS spectrum or do not consider the spectra's shape change across time. Here we present a new statistical approach named SABARSI that overcomes these difficulties by combining information from multiple spectra.

Untargeted Tumor Metabolomics with Liquid Chromatography-Surface-Enhanced Raman Spectroscopy.

Metabolomics is a powerful systems biology approach that monitors changes in biomolecule concentrations to diagnose and monitor health and disease. However, leading metabolomics technologies, such as NMR and mass spectrometry (MS), access only a small portion of the metabolome. Now an approach is presented that uses the high sensitivity and chemical specificity of surface-enhanced Raman scattering (SERS) for online detection of metabolites from tumor lysates following liquid chromatography (LC).

The CXCL5/CXCR2 axis is sufficient to promote breast cancer colonization during bone metastasis.

Bone is one of the most common sites for metastasis across cancers. Cancer cells that travel through the vasculature and invade new tissues can remain in a non-proliferative dormant state for years before colonizing the metastatic site. Switching from dormancy to colonization is the rate-limiting step of bone metastasis.

Death effector domain-containing protein induces vulnerability to cell cycle inhibition in triple-negative breast cancer.

Lacking targetable molecular drivers, triple-negative breast cancer (TNBC) is the most clinically challenging subtype of breast cancer. In this study, we reveal that Death Effector Domain-containing DNA-binding protein (DEDD), which is overexpressed in > 60% of TNBCs, drives a mitogen-independent G1/S cell cycle transition through cytoplasm localization. The gain of cytosolic DEDD enhances cyclin D1 expression by interacting with heat shock 71 kDa protein 8 (HSC70).

Potassium channel activity controls breast cancer metastasis by affecting β-catenin signaling.

Potassium ion channels are critical in the regulation of cell motility. The acquisition of cell motility is an essential parameter of cancer metastasis. However, the role of K channels in cancer metastasis has been poorly studied.

Metabolomics of oncogene-specific metabolic reprogramming during breast cancer.

Background: The complex yet interrelated connections between cancer metabolism and oncogenic driver genes are relatively unexplored but have the potential to identify novel biomarkers and drug targets with prognostic and therapeutic value. The goal of this study was to identify global metabolic profiles of breast tumors isolated from multiple transgenic mouse models and to identify unique metabolic signatures driven by these oncogenes.

Methods: Using mass spectrometry (GC-MS, LC-MS/MS, and capillary zone electrophoresis (CZE)-MS platforms), we quantified and compared the levels of 374 metabolites in breast tissue from normal and transgenic mouse breast cancer models overexpressing a panel of oncogenes (PyMT, PyMT-DB, Wnt1, Neu, and C3-TAg).

Discoidin domain receptor 1 (DDR1) ablation promotes tissue fibrosis and hypoxia to induce aggressive basal-like breast cancers.

The discoidin domain receptor 1 (DDR1) is overexpressed in breast carcinoma cells. Low DDR1 expression is associated with worse relapse-free survival, reflecting its controversial role in cancer progression. We detected DDR1 on luminal cells but not on myoepithelial cells of DDR1 mice.

The AKT inhibitor triciribine in combination with paclitaxel has order-specific efficacy against Zfp217-induced breast cancer chemoresistance.

We previously identified the transcription factor ZNF217 (human) / Zfp217 (mouse) as an oncogene and prognostic indicator of reduced survival, increased metastasis, and reduced response to therapy in breast cancer patients. Here we investigated the role of Zfp217 in chemotherapy resistance. Preclinical animal models of Zfp217 overexpression were treated with a combination therapy of the microtubule inhibitor epothilone B, doxorubicin (Adriamycin), and cyclophosphamide (EAC).

Tumor infiltrating leukocyte density is independent of tumor grade and molecular subtype in aggressive breast cancer of Western Kenya.

Background: Tumors commonly are infiltrated by leukocytes, or tumor infiltrating leukocytes (TILs). It remains unclear, however, if the density and type of individual TILs has a direct or simply correlative role in promoting poor prognosis in breast cancer patients. Breast cancer in Kenyan women is aggressive with presentation at a young age, with advanced grade (grade III), large tumor size (>2.

Bone: A Fertile Soil for Cancer Metastasis.

Bone is one of the most common and most dangerous sites for metastatic growth across cancer types, and bone metastasis remains incurable. Unfortunately, the processes by which cancers preferentially metastasize to bone are still not well understood. In this review, we summarize the morphological features, physical properties, and cell signaling events that make bone a unique site for metastasis and bone remodeling.

Aggressive breast cancer in western Kenya has early onset, high proliferation, and immune cell infiltration.

Background: Breast cancer incidence and mortality vary significantly among different nations and racial groups. African nations have the highest breast cancer mortality rates in the world, even though the incidence rates are below those of many nations. Differences in disease progression suggest that aggressive breast tumors may harbor a unique molecular signature to promote disease progression.

Patient-Derived Tumor Xenograft Models of Breast Cancer.

The need for model systems that more accurately predict patient outcome has led to a renewed interest and a rapid development of orthotopic transplantation models designed to grow, expand, and study patient-derived human breast tumor tissue in mice. After implanting a human breast tumor piece into a mouse mammary fat pad and allowing the tumor to grow in vivo, the tumor tissue can be either harvested and immediately implanted into mice or can be stored as tissue pieces in liquid nitrogen for surgical implantation at a later time. Here, we describe the process of surgically implanting patient-derived breast tumor tissue into the mammary gland of nonobese diabetic-severe combined immunodeficiency (NOD-SCID) mice and harvesting tumor tissue for long-term storage in liquid nitrogen.

Global analysis of ZNF217 chromatin occupancy in the breast cancer cell genome reveals an association with ERalpha.

Background: The ZNF217 gene, encoding a C2H2 zinc finger protein, is located at 20q13 and found amplified and overexpressed in greater than 20% of breast tumors. Current studies indicate ZNF217 drives tumorigenesis, yet the regulatory mechanisms of ZNF217 are largely unknown. Because ZNF217 associates with chromatin modifying enzymes, we postulate that ZNF217 functions to regulate specific gene signaling networks.

A role for matrix metalloproteinases in regulating mammary stem cell function via the Wnt signaling pathway.

The microenvironment provides cues that control the behavior of epithelial stem and progenitor cells. Here, we identify matrix metalloproteinase-3 (MMP3) as a regulator of Wnt signaling and mammary stem cell (MaSC) activity. We show that MMP3 overexpression promotes hyperplastic epithelial growth, surprisingly, in a nonproteolytic manner via its hemopexin (HPX) domain.

The transcription factor ZNF217 is a prognostic biomarker and therapeutic target during breast cancer progression.

Unlabelled: The transcription factor ZNF217 is a candidate oncogene in the amplicon on chromosome 20q13 that occurs in 20% to 30% of primary human breast cancers and that correlates with poor prognosis. We show that Znf217 overexpression drives aberrant differentiation and signaling events, promotes increased self-renewal capacity, mesenchymal marker expression, motility, and metastasis, and represses an adult tissue stem cell gene signature downregulated in cancers. By in silico screening, we identified candidate therapeutics that at low concentrations inhibit growth of cancer cells expressing high ZNF217.