Medical Sciences Commons^™

'Educated' Osteoblasts Reduce Osteoclastogenesis In A Bone-Tumor Mimetic Microenvironment., Alexus D. Kolb, Jinlu Dai, Evan T. Keller, Karen M. Bussard

Department of Cancer Biology Faculty Papers

Breast cancer (BC) metastases to bone disrupt the balance between osteoblasts and osteoclasts, leading to excessive bone resorption. We identified a novel subpopulation of osteoblasts with tumor-inhibitory properties, called educated osteoblasts (EOs). Here we sought to examine the effect of EOs on osteoclastogenesis during tumor progression. We hypothesized that EOs affect osteoclast development in the bone-tumor niche, leading to suppressed pre-osteoclast fusion and bone resorption. Conditioned media (CM) was analyzed for protein expression of osteoclast factors receptor activator of nuclear factor kappa-β ligand (RANKL), osteoprotegerin (OPG), and tumor necrosis factor alpha (TNFα) via ELISA. EOs were co-cultured with pre-osteoclasts on …

Il-15/Il-15rα Heterodimeric Complex As Cancer Immunotherapy In Murine Breast Cancer Models, Siqi Guo, Ronald B. Smeltz, Anthony Nanajian, Richard Heller

Bioelectrics Publications

Interleukin 15 (IL-15) has been evaluated as a potential treatment for solid tumors in clinical trials, but the effectiveness of systemic IL-15 administration as a monotherapy has not been realized. IL-15 receptor alpha (IL-15Rα) can stabilize IL-15 and enhance its bioactivity. The goal of this study was to examine the activity of IL-15/IL-15Rα complex (IL-15cx) to CD8(+) T cells and evaluate its potential efficacy in murine breast cancer models. The antitumor efficacy was studied in mouse mammary carcinoma models (Her2/neu transgenic and 4T1-luc mammary cancers) treated with systemic recombinant protein with/without the depletion of myeloid-derived suppressor cells or intra-tumoral gene …

Endogenous Cyclin D1 Promotes The Rate Of Onset And Magnitude Of Mitogenic Signaling Via Akt1 Ser473 Phosphorylation., Ke Chen, Xuanmao Jiao, Agnese Di Rocco, Duanwen Shen, Shaohua Xu, Adam Ertel, Zuoren Yu, Gabriele Di Sante, Min Wang, Zhiping Li, Timothy G Pestell, Mathew C Casimiro, Emmanuel Skordalakes, Samuel Achilefu, Richard G Pestell

Department of Cancer Biology Faculty Papers

Cyclin D1 encodes the regulatory subunit of a holoenzyme that phosphorylates RB and functions as a collaborative nuclear oncogene. The serine threonine kinase Akt plays a pivotal role in the control of cellular metabolism, survival, and mitogenic signaling. Herein, Akt1-mediated phosphorylation of downstream substrates in the mammary gland is reduced by cyclin D1 genetic deletion and is induced by mammary-gland-targeted cyclin D1 overexpression. Cyclin D1 is associated with Akt1 and augments the rate of onset and maximal cellular Akt1 activity induced by mitogens. Cyclin D1 is identified in a cytoplasmic-membrane-associated pool, and cytoplasmic-membrane-localized cyclin D1-but not nuclear-localized cyclin D1-recapitulates Akt1 …

Novel Role For The Golgi Membrane Protein Tmem165 In Control Of Migration And Invasion For Breast Carcinoma, Pavitra Murali, Blake P. Johnson, Zhongpeng Lu, Leslie Climer, Danielle A. Scott, Francois Foulquier, Gabriela Oprea-Ilies, Vladimir Lupashin, Richard R. Drake, Karen L. Abbott

Articles

The TMEM165 gene encodes for a multiple pass membrane protein localized in the Golgi that has been linked to congenital disorders of glycosylation. The TMEM165 protein is a putative ion transporter that regulates H+/Ca++/Mn++ homeostasis and pH in the Golgi. Previously, we identified TMEM165 as a potential biomarker for breast carcinoma in a glycoproteomic study using late stage invasive ductal carcinoma tissues with patient-matched adjacent normal tissues. The TMEM165 protein was not detected in non-malignant matched breast tissues and was detected in invasive ductal breast carcinoma tissues by mass spectrometry. Our hypothesis is that the TMEM165 protein confers a growth …

The Bone Extracellular Matrix As An Ideal Milieu For Cancer Cell Metastases., Alexus D. Kolb, Karen M. Bussard

Department of Cancer Biology Faculty Papers

Bone is a preferential site for cancer metastases, including multiple myeloma, prostate, and breast cancers.The composition of bone, especially the extracellular matrix (ECM), make it an attractive site for cancer cell colonization and survival. The bone ECM is composed of living cells embedded within a matrix composed of both organic and inorganic components. Among the organic components, type I collagen provides the tensile strength of bone. Inorganic components, including hydroxyapatite crystals, are an integral component of bone and provide bone with its rigidity. Under normal circumstances, two of the main cell types in bone, the osteoblasts and osteoclasts, help to …

Differential Iron Regulatory Genetics In 2d & 3d Culture Of Breast Cancer Cells, Tyler Hanna, Suzy Torti Ph. D, Frank Torti M.D., Mph, Nicole Farra Ph. D.

Honors Scholar Theses

The iron regulatory axis has consistently been shown to be perturbed in cancer cell lines relative to non-cancerous cell lines. As cancer cells rapidly divide and grow, they require iron to fuel many intracellular processes, including DNA replication and protein synthesis. Three-dimensional cell culture is an increasingly popular method of culture that purportedly more accurately mimics the in vivo microenvironment of cancers over traditional two-dimensional culture. This project was prompted by previous lab results to investigate differential iron regulatory gene expression in 2D and 3D spheroid culture models. We replicated the findings that the gene hepcidin is induced in 3D …

Investigating The Involvement Of Runx1 And Hif-1Α In Hypoxia-Induced Epithelial-To-Mesenchymal Transition And Generation Of Breast Cancer Stem Cells, Lizzi Hahn

Larner College of Medicine Fourth Year Advanced Integration Teaching/Scholarly Projects

No abstract provided.

Development Of Rational Combination Therapy With Parp Inhibitors And Kinase Inhibitors In Tnbc, Wen-Hsuan Yu

Dissertations & Theses (Open Access)

Poly (ADP-ribose) polymerase inhibitors (PARPi) emerge as potential targeting drugs for BRCA-deficient cancers including triple negative breast cancer (TNBC). However, it has been reported that a subgroup of patients even with BRCA mutation fails to respond to PARPi in multiple clinical trials. In this study, we identified c-Met, a tyrosine kinase, phosphorylates PARP1 at Y907 and that the phosphorylation increases PARP1 activity, thereby rendering cancer cells resistant to PARPi. The combination of c-Met inhibitors (METi) and PARPi has a synergistic effect for c-Met overexpressed TNBC in vitro and in vivo. In addition to c-Met, through functional analysis, we found …

The Role Of Cytoplasmic Polyadenylation Element Binding Protein-2 (Cpeb-2) In Breast Cancer, Asma Hasan

Electronic Thesis and Dissertation Repository

Over-expression of inflammation associated enzyme cyclo-oxygenase (COX)-2 promotes breast cancer progression, metastasis and sustains cancer stem-like cells (SLCs) by activating prostaglandin E₂ receptor EP4. Two COX-2 induced oncogenic miRNAs, miR-655 and miR-526b, target and down-regulate the cytoplasmic polyadenylation element binding protein (CPEB)-2. Hypothesis: Down-regulation of CPEB2 promotes an aggressive breast cancer phenotype through SLC induction and epithelial to mesenchymal transition (EMT). We found that high COX-2/miRNA expressing cell lines MDAMB231 and MCF7-COX-2 had significantly lower expression of CPEB2 than MCF7 cells (low COX-2/miRNA). CPEB2 knockdown in CPEB2-high MCF7 cell line resulted in increased migratory and invasive capacity in …

Numerical Simulation Of Terahertz Wave Interaction With Breast Cancer Tumor Tissue Sections, Abayomi Omotola Omolewu

Graduate Theses and Dissertations

This thesis presents numerical simulation of terahertz (THz) wave interaction with breast cancer tumor tissue sections. The obtained results are expressed in THz images of heterogeneous material that mimics the excised breast cancer tissue sections. The finite-element software package ANSYS High Frequency Structural Simulator (HFSS) was used in this work. HFSS is a full wave frequency domain three-dimensional (3D) electromagnetic simulation package. In this work, four breast cancer tissue models based on pathology images were simulated and images of the models were obtained at 1 THz. An incident Gaussian beam was raster scanned over tissue model configurations and the reflected …

The Role Of Bone-Derived Osteopontin In The Migration And Stem-Like Behavior Of Breast Cancer Cells, Graciella Pio

Electronic Thesis and Dissertation Repository

The majority of breast cancer deaths occur due to metastasis, with the most common site of breast cancer metastasis being bone. Previous work in our laboratory has established that stem-like breast cancer cells with high aldehyde dehydrogenase (ALDH) activity and expression of a CD44⁺CD24^- phenotype have enhanced metastatic capacity. This study tested the hypothesis that bone-derived osteopontin (OPN) promotes the migration and stem-like behavior of breast cancer cells. We demonstrate that bone- derived OPN promotes migration, tumorsphere-forming ability and colony-forming ability of whole population and ALDH^hiCD44⁺CD24^- breast cancer cells in bone marrow- …

Mir-17/20 Sensitization Of Breast Cancer Cells To Chemotherapy-Induced Apoptosis Requires Akt1., Zuoren Yu, Zengguang Xu, Gabriele Disante, Jennifer Wright, Min Wang, Yuan Li, Qian Zhao, Tao Ren, Xiaoming Ju, Ellen Gutman, Guangxue Wang, Sankar Addya, Tieyan Li, Zhendong Xiang, Chenguang Wang, Xiongfei Yang, Xiaolai Yang, Richard Pestell

Department of Cancer Biology Faculty Papers

The serine threonine kinase Akt1 has been implicated in the control of cellular metabolism, survival and growth. Herein, disruption of the ubiquitously expressed member of the Akt family of genes, Akt1, in the mouse, demonstrates a requirement for Akt1 in miRNA-mediated cellular apoptosis. The miR-17/20 cluster is known to inhibit breast cancer cellular proliferation through G1/S cell cycle arrest via binding to the cyclin D1 3'UTR. Here we show that miR-17/20 overexpression sensitizes cells to apoptosis induced by either Doxorubicin or UV irradiation in MCF-7 cells via Akt1. miR-17/20 mediates apoptosis via increased p53 expression which promotes Akt degradation. Akt1-/- …

A Potential Mechanism For Extracellular Matrix Induction Of Breast Cancer Cell Normality, Robert D. Bruno, Gilbert H. Smith

Medical Diagnostics & Translational Sciences Faculty Publications

Extracellular matrix proteins from embryonic mesenchyme have a normalizing effect on cancer cells in vitro and slow tumor growth in vivo. This concept is suggestive of a new method for controlling the growth and spread of existing cancer cells in situ and indicates the possibility that extracellular proteins and/or embryonic mesenchymal fibroblasts may represent a fertile subject for study of new anti-cancer treatments.

Endothelial Cell Pseudopods And Angiogenesis Of Breast Cancer Tumors, Ivan Cameron, Nicholas Short, Luzhe Sun, W. Hardman

Elaine Hardman Ph.D.

Background A neoplastic tumor cannot grow beyond a millimeter or so in diameter without recruitment of endothelial cells and new blood vessels to supply nutrition and oxygen for tumor cell survival. This study was designed to investigate formation of new blood vessels within a human growing breast cancer tumor model (MDA MB231 in mammary fat pad of nude female mouse). Once the tumor grew to 35 mm3, it developed a well-vascularized capsule. Histological sections of tumors greater than 35 mm3were stained with PAS, with CD-31 antibody (an endothelial cell maker), or with hypoxia inducible factor 1α antibody (HIF). The extent …

Therapeutic Electromagnetic Field (Temf) And Gamma Irradiation On Human Breast Cancer Xenograft Growth, Angiogenesis And Metastasis, Ivan L. Cameron, Luzhe Sun, Nicholas Short, W. Elaine Hardman, C. Douglas Williams

Elaine Hardman Ph.D.

Background The effects of a rectified semi-sinewave signal (15 mT amplitude, 120 pulses per second, EMF Therapeutics, Inc.) (TEMF) alone and in combination with gamma irradiation (IR) therapy in nude mice bearing a human MDA MB231 breast cancer xenograft were tested. Green fluorescence protein transfected cancer cells were injected into the mammary fat pad of young female mice. Six weeks later, mice were randomly divided into four treatment groups: untreated controls; 10 minute daily TEMF; 200 cGy of IR every other day (total 800 cGy); IR plus daily TEMF. Some mice in each group were euthanized 24 hours after the …

High Dietary Level Of Synthetic Vitamin E On Lipid Peroxidation, Membrane Fatty Acid Composition And Cytotoxicity In Breast Cancer Xenograft And In Mouse Host Tissue, Ivan L. Cameron, Jesus Munoz, Christopher J. Barnes, W. Elaine Hardman

Elaine Hardman Ph.D.

Background d-α-tocopherol is a naturally occurring form of vitamin E not previously known to have antitumor activity. Synthetic vitamin E (sE) is a commonly used dietary supplement consisting of a mixture of d-α-tocopherol and 7 equimolar stereoisomers. To test for antilipid peroxidation and for antitumor activity of sE supplementation, two groups of nude mice bearing a MDA-MB 231 human breast cancer tumor were fed an AIN-76 diet, one with and one without an additional 2000 IU/kg dry food (equivalent to 900 mg of all-rac-α-tocopherol or sE). This provided an intake of about 200 mg/kg body weight per day. The mice …

The Role Of Ptip In Breast Cancer, Lina Niu

Theses, Dissertations and Capstones

In the U.S., breast cancer comprises about 30% of all cancer cases (excluding skin cancer) in women. Such a high incidence makes breast cancer a significant health concern, but our understanding of the molecular and cellular mechanisms of this disease is still limited. Growing evidence suggests that the development of human breast cancer may involve epigenetics, which attributes changes in phenotype to mechanisms other than changes in the DNA sequence itself. Histones as the chief proteins of chromatin work on gene expression, and methylation of histone 3 lysine 4 (H3K4) results in transcriptional activation. Lately, Paired box (Pax) trans-activation domain-interacting …

C-Abl And Arg Drive Cancer Chemoresistance Via Activation Of Multiple Signaling Pathways, Jonathan Thomas Sims

Theses and Dissertations--Pharmacology and Nutritional Sciences

Despite 35 years of clinical trials, there has been little improvement in one-year survival rates with any chemotherapeutic regimen for the treatment of metastatic melanoma due to resistance to all known agents. Regardless of advances in detection and prevention, diagnosis of metastatic disease remains a death sentence. Resistance mechanisms, including aberrant kinase signaling and drug transport pumps, indicate a need for identification of other therapeutic targets that impinge upon multiple signaling pathways. The Abl family of non-receptor tyrosine kinases (c-Abl, Arg) has been indicted as a causative force in leukemia for more than three decades; however, their role in solid …

Therapeutic Electromagnetic Field (Temf) And Gamma Irradiation On Human Breast Cancer Xenograft Growth, Angiogenesis And Metastasis, Ivan L. Cameron, Luzhe Sun, Nicholas Short, W. Elaine Hardman, C. Douglas Williams

Biochemistry and Microbiology

Background

The effects of a rectified semi-sinewave signal (15 mT amplitude, 120 pulses per second, EMF Therapeutics, Inc.) (TEMF) alone and in combination with gamma irradiation (IR) therapy in nude mice bearing a human MDA MB231 breast cancer xenograft were tested. Green fluorescence protein transfected cancer cells were injected into the mammary fat pad of young female mice. Six weeks later, mice were randomly divided into four treatment groups: untreated controls; 10 minute daily TEMF; 200 cGy of IR every other day (total 800 cGy); IR plus daily TEMF. Some mice in each group were euthanized 24 hours after the …

Endothelial Cell Pseudopods And Angiogenesis Of Breast Cancer Tumors, Ivan L. Cameron, Nicholas Short, Luzhe Sun, W. Elaine Hardman

Biochemistry and Microbiology

Background

A neoplastic tumor cannot grow beyond a millimeter or so in diameter without recruitment of endothelial cells and new blood vessels to supply nutrition and oxygen for tumor cell survival. This study was designed to investigate formation of new blood vessels within a human growing breast cancer tumor model (MDA MB231 in mammary fat pad of nude female mouse). Once the tumor grew to 35 mm³, it developed a well-vascularized capsule. Histological sections of tumors greater than 35 mm³were stained with PAS, with CD-31 antibody (an endothelial cell maker), or with hypoxia inducible factor 1α …

High Dietary Level Of Synthetic Vitamin E On Lipid Peroxidation, Membrane Fatty Acid Composition And Cytotoxicity In Breast Cancer Xenograft And In Mouse Host Tissue, Ivan L. Cameron, Jesus Munoz, Christopher J. Barnes, W. Elaine Hardman

Biochemistry and Microbiology

Background

d-α-tocopherol is a naturally occurring form of vitamin E not previously known to have antitumor activity. Synthetic vitamin E (sE) is a commonly used dietary supplement consisting of a mixture of d-α-tocopherol and 7 equimolar stereoisomers. To test for antilipid peroxidation and for antitumor activity of sE supplementation, two groups of nude mice bearing a MDA-MB 231 human breast cancer tumor were fed an AIN-76 diet, one with and one without an additional 2000 IU/kg dry food (equivalent to 900 mg of all-rac-α-tocopherol or sE). This provided an intake of about 200 mg/kg body weight per day. The mice …