Rosemarie D'Angelo

 Rosemarie D'Angelo

Rosemarie D'Angelo

  • Courses1
  • Reviews2

Biography

Macomb Community College ALL - Biology


Resume

  • 2017

    Faculty Representative

    College Diabetes Network

  • 2011

    Poster Presentation at 2 Conferences/Meetings:\nCancer Research Symposium Poster

    University of Michigan Comprehensive Cancer Center

    Ann Arbor

    MI. Dec 17

    2010\nAACR Annual Meeting April 2-6

    Therapeutic targeting of the Notch pathway in breast cancer stem cells.

    Abstract\nThis study identified CD63

    a member of the tetraspanin family

    as a TIMP-1 interacting protein by yeast two-hybrid screening. Immunoprecipitation and confocal microscopic analysis confirmed CD63 interactions with TIMP-1

    integrin beta1

    and their co-localizations on the cell surface of human breast epithelial MCF10A cells. TIMP-1 expression correlated with the level of active integrin beta1 on the cell surface independent of cell adhesion. While MCF10A cells within a three-dimensional (3D) matrigel matrix form polarized acinar-like structures

    TIMP-1 overexpression disrupted breast epithelial cell polarization and inhibited caspase-mediated apoptosis in centrally located cells

    necessary for the formation and maintenance of the hollow acinar-like structures. Small hairpin RNA (shRNA)-mediated CD63 downregulation effectively reduced TIMP-1 binding to the cell surface

    TIMP-1 co-localization with integrin beta1

    and consequently reversed TIMP-1-mediated integrin beta1 activation

    cell survival signaling and apoptosis inhibition. CD63 downregulation also restored polarization and apoptosis of TIMP-1 overexpressing MCF10A cells within a 3D-matrigel matrix. Taken together

    the present study identified CD63 as a cell surface binding partner for TIMP-1

    regulating cell survival and polarization via TIMP-1 modulation of tetraspanin/integrin signaling complex.

    Identification of CD63 as a tissue inhibitor of metalloproteinase-1 interacting cell surface protein.

    Rosemarie

    Wayne State University School of Medicine

    Karmanos Cancer Institute

    University of Michigan - Research and Sponsored Projects

    National Science Foundation (NSF)

    Macomb Community College

    Marygrove College

    Oakland University

    PRECISIONscientia

    National Science Foundation Faculty Institutes for Reforming Science Teaching (FIRST IV) Fellowship

    •\tChosen to participate in a professional development program for postdoctoral fellows interested in learning the evidence-based research behind the science of teaching and learning and STEM education reform\n•\tAttended two

    all expenses paid summer workshops

    designed and taught a student-centered biology course in a cooperative group and received feedback on teaching experience

    Science of Teaching and Learning

    University of Michigan

  • 2009

    Postdoctoral Fellow at Comprehensive Cancer Center

    Internal Medicine (Hematology/Oncology)

    University of Michigan

  • 2007

    Member of Women in Cancer Group

    Associate Member

    American Association of Cancer Research

    Spanish

    Lilly Conference Travel Grant for Presentation of Oral Presentation

    Center for Teaching and Learning at Oakland University

    The DOD Era of Hope Meeting

    Poster Presentation

    Baltimore

    MD

    Department of Defense

    WSU School of Medicine Outstanding Graduate Student Award

    $500

    Wayne State University School of Medicine

    National Cancer Institute (NCI)

    Ruth L. Kirschstein National Research Service Award Institutional Research Training (T32) Fellowship

    $42

    000/year

    National Cancer Institute

    U.S. Army Medical Research and Materiel Command (USAMRMC)

    Department of Defense (DOD) Breast Cancer Research Program (BCRP) Predoctoral Traineeship Award

    $30

    000/year

    Department of Defense

    The Edward A. Smuckler Memorial Workshop: Pathobiology of Cancer (AACR) Workshop in Cancer Research

    Snowmass Village

    CO

    An intensive one-week course with gross and microscopic diagnostic training devoted to normal histology and cancer of the major organ systems including: (1) hematopoietic tissues (2) gastrointestinal tract; (3) childhood tumors and brain; (4) breast

    uterus

    cervix

    and ovary; (5) male genitourinary tract; and (6) lung and skin.

    American Association for Cancer Research

  • 2006

    Student Representative for my program

    Student Member of Cancer Biology Curriculum Committee

    American Association for the Advancement of Science (AAAS)

  • 2005

    Student Representative for Cancer Biology Program at Wayne State

  • 2003

    Doctor of Philosophy - PhD

    Cancer Biology

    Wayne State University School of Medicine

    GPA 3.9

  • 2001

    Master of Science - MS

    \n

    Basic Medical Sciences

    Wayne State University School of Medicine

    GPA 3.7

  • 1996

    Bachelor of Science - BS

    Human Biology

    Michigan State University

    GPA 3.4

    Community Engaged Research Training

    Law

    Values

    and Healthcare (Bioethics)

    Human Genetics

    Introduction to Organic and Biochemistry

    Health in Personal and Occupational Enviornments

    Human Pathology

    Nutrient Metabolism

    Anatomy and Physiology

    LinkedIn

    Betty Liu on Career Success

    Jodi Glickman on Pitching Yourself

    LinkedIn

    Association of Clinical Research Professionals: Introduction to Clinical Research Webinar Training

    Giving Your Elevator Pitch

    LinkedIn

    NIDA Training in Good Clinical Practice Guidelines

    Negotiating Your Job Offer

    LinkedIn

    The Edward A. Smuckler Memorial Workshop: Pathobiology of Cancer (AACR) Workshop in Cancer Research

    Snowmass Village

    CO

  • 500.

    Detroit

    MI

    Essay Advisors: Richard Everson

    M.D.

    M.P.H & James Eliason

    Ph.D.\nEssay Project: Using the Comet Assay to Observe DNA Damage of Breast Cancer Cells after Treatment with Chemotherapeutic Drugs\n\n•\tHigh collaboration skills working with the biotech company Asterand to separate out tumor cells from frozen bone marrow of patients that underwent chemotherapy to study resistance resulting in awarding of the WSU Graduate Student Fellowship

    $2

    Graduate Research Assistant M.S. in Basic Medical Sciences Program

    Karmanos Cancer Institute

    Kellogg Biological Research Station (Hickory Corners

    MI)

    NSF FIRST IV Fellowship

    Co-Principle Investigators of the NSF grant: Diane Ebert-May

    Ph.D. (Michigan State University

    East Lansing

    MI) &Terry Derting

    Ph.D. (Murray State University

    Murray

    KY \n•\tStrong development of professional skills after being chosen to participate in a competitive program for postdoctoral fellows interested in STEM education reform.\n•\tAttended two

    all expenses paid summer workshops

    designed and taught Human Genetics for the Molecular Cellular and Developmental Biology Department

    University of Michigan

    Ann Arbor

    MI (Summer 2011)

    and received feedback on teaching experience.

    Postdoctoral Teaching Fellow and Intermittent Lecturer

    National Science Foundation (NSF)

    Warren

    Michigan

    Arts and Sciences Department\nMacomb Community College South Campus\n\n•\tKnowledgeable curriculum designer and developer using backward design and learning outcomes for assessments and activities in an Introductory lecture and laboratory Biology course.\n•\tStrong leadership and technological skills resulting in being chosen as the first adjunct to teach Anatomy and Physiology using the Willey-Plus publisher web-based learning platform.

    Adjunct Professor

    Macomb Community College

    Precision Medicine Group Inc. acquired ETHOS Health Communications

    a Pennsylvania-based agency that specializes in the interpretation and communication of innovative medical science in 2018. ETHOS Health Communications is now known as PRECISIONscientia.

    PRECISIONscientia

    Wayne State University School of Medicine

    Detroit

    MI

    Graduate Research Assistant Cancer Biology Program\nDissertation Mentor: Hyeong-Reh Choi Kim

    Ph.D. \nDissertation Project: The Novel Functions of the Tissue Inhibitor of Metalloproteinase (TIMP-1): Inhibition of Apoptosis and Induction of an Epithelial-Mesenchymal Transition\n\n•\tExcellent science writer and collaborator contributing to NIH RO1 grants (1.9 million) and 2 first author and 2 contributing publications including an individual U.S. Army Department of Defense Breast Cancer Research Program Predoctoral Traineeship Award

    $30

    000/year.\n•\tExpertise in technical

    market-knowledge

    and problem-solving skills in molecular genetics and cellular biology techniques contributing to the design of established protocols in the laboratory.\n•\tHigh-level project management and leadership skills demonstrated by the training of students working in the laboratory resulting in summer fellowships and acceptance into medical school.\n•\tStrong communication skills resulting in winning of graduate student and Scholar in Training awards leading to invitations to present research at international (AACR) and local meetings.\n•\tStrong relationship builder with health care practitioners and KOLs while doing clinical rotations of oncologists at Karmanos Cancer Institute resulting in interest in translational cancer research.

    Project Manager and Medical Writer Experience

    Ann Arbor

    MI

    Postdoctoral Fellow\nUniversity of Michigan Comprehensive Cancer Center\nPrinciple Investigator: Max Wicha

    M.D.\nProjects: Activation and Tumorigenesis of Notch Stem Cell Pathway in Breast Cancer Cells and Identification of Cancer Stem Cell Biomarkers in Normal Mammary Tissue\n\n•\tExcellent teamwork and project management skills working on several multifaceted research projects resulting in two first author journal publications

    3 contributing author publications

    and \nNational Cancer Institute (NCI) Research Training (T32) Fellowship

    $42

    000/year.\no\tMember of the Stand Up to Cancer Dream Team resulting in the sharing of $73 million dollars towards new treatments from lab to cancer patient.\n•\tRelationship builder with Merck to conduct preclinical tumor imaging studies using cell lines and NOD/SCID mice for drug development of a Gamma Secretase Inhibitor (GSI) against the Notch pathway leading to establishment of new therapeutic combinations against breast cancer.\n•\tHigh-level technical and problem-solving skills demonstrated in the process of generating cells from reduction mammoplasties resulting in the development of complex multi-color flow cytometry biomarker protocols.\n•\tStrong leadership skills demonstrated in the teaching of daily research activities

    project development

    and writing of fellowship applications leading to specialized training of undergraduate students

    visiting medical fellows

    researchers

    and pathologists.\n•\tKnowledge of current industry trends and experience communicating complex topics to diverse audiences resulting in presentations at international meetings like AACR.

    Project Manager and Medical Writer Experience

    University of Michigan - Research and Sponsored Projects

    Detroit

    MI

    Science and Math Department\nMarygrove College\n\n•\tStrong team player and communicator working with other adjunct and full-time faculty leading to uniformity among assessments in 2 sections of an Introductory Biology course.\n•\tExcellent resource and time management skills responsible for the development and organization of all sections of Introductory Biology laboratories resulting in newer inquiry-based lab exercises.\n•\tStrong leadership skills resulting in being chosen as first adjunct to co-teach Introduction to Organic and Biochemistry

    focusing on the Biochemistry portion of the course.\n•\tCompetent technological skills utilizing online materials from McGraw Hill Connect websites for Biology and Biochemistry resulting in decreased assessment development and grading time.

    Adjunct Professor

    Marygrove College

    Rochester

    MI

    Interdisciplinary Health\nOakland University School of Health Sciences\n\n•\tHigh level educator with diverse teaching and curriculum development on the prevention

    management

    and treatment of diseases resulting in the training of Health Science students.\n•\tExcellent interdisciplinary collaboration skills demonstrated working in cross functional teams to design assessments and train 6 undergraduate student graders to maximize grading efficiency.\n•\tExpanded professional awareness and development in evidence-based learning in STEM fields including: flipping the classroom

    adult learning theory

    active and problem-based learning resulting in a learner-centered approach to teaching.\n•\tStrong project management skills in community research demonstrated by planning 5 individual and one large community class project for the Parks and Recreation Department of Pontiac

    MI.\n•\tPassionate presentation and communication skills demonstrated at oral sessions at local and national conferences including awarding of a travel grant to a Lilly teaching conference ($1

    200).

    Visiting Assistant Professor

    Oakland University

  • 500

    WSU School of Medicine Graduate Student Research Fellowship

    $2

    Wayne State University School of Medicine

    NCI (T32) Fellowship

    declined due to overlap with DOD Traineeship

    National Cancer Institute

    WSU School of Medicine Research Award for Best Oral Presentation

    $800

    Wayne State University School of Medicine

  • 000

    WSU Graduate Student External Support Award

    $2

    Wayne State University School of Medicine

    NSF FIRST IV Fellowship

    1/2011-6/2012\t

    National Science Foundation

    AACR-Aflac

    Scholar-in-Training Award for Associate Members

    $1000

    American Association for Cancer Research

    NIH Graduate Student Research Festival Poster Presentation

    Bethesda

    MD

    National Institute of Health

  • Karmanos Cancer Institute

    Sexual Health Counselor

    Assist and shadow the doctor with pap smear testing and education and counseling on sexually transmitted infections and methods of contraception for college students and uninsured patients at Michigan State University.

    Gateway Community Health Clinic East Lansing

    MI

    First Response Counselor

    Education and counseling for victims of rape and violence.

    Turning Point

    Medical education and communications

    Molecular Biology

    Medicine

    Clinical Research

    Biotechnology

    Higher Education

    Pre-Clinical/Translational Research

    Immunology

    U.S. Health Insurance Portability and Accountability Act (HIPAA)

    Western Blotting

    Oncology

    Grant Writing

    Project Management

    Biochemistry

    Good Clinical Practice (GCP)

    Cell Culture

    Life Sciences

    Cell Biology

    Strategic Planning

    Pharmaceutical Industry

    Breast cancer stem cells transition between epithelial and mesenchymal states reflective of their normal counterparts.

    Abstract\nPrevious studies have suggested that breast cancer stem cells (BCSCs) mediate metastasis

    are resistant to radiation and chemotherapy

    and contribute to relapse. Although several BCSC markers have been described

    it is unclear whether these markers identify the same or independent BCSCs. Here

    we show that BCSCs exist in distinct mesenchymal-like (epithelial-mesenchymal transition [EMT]) and epithelial-like (mesenchymal-epithelial transition [MET]) states. Mesenchymal-like BCSCs characterized as CD24(-)CD44(+) are primarily quiescent and localized at the tumor invasive front

    whereas epithelial-like BCSCs express aldehyde dehydrogenase (ALDH)

    are proliferative

    and are located more centrally. The gene-expression profiles of mesenchymal-like and epithelial-like BCSCs are remarkably similar across different molecular subtypes of breast cancer

    and resemble those of distinct basal and luminal stem cells found in the normal breast. We propose that the plasticity of BCSCs that allows them to transition between EMT- and MET-like states endows these cells with the capacity for tissue invasion

    dissemination

    and growth at metastatic sites.

    Breast cancer stem cells transition between epithelial and mesenchymal states reflective of their normal counterparts.

    Abstract\nMatrix metalloproteinases (MMPs) and their endogenous inhibitors (TIMPs) regulate epithelial-mesenchymal transition (EMT) critical for the development of epithelial organs as well as cancer cell invasion. TIMP-1 is frequently overexpressed in several types of human cancers and serves as a prognostic marker. The present study investigates the roles of TIMP-1 on the EMT process and formation of the lumen-like structure in a 3D Matrigel culture of MDCK cells. We show that TIMP-1 overexpression effectively prevents cell polarization and acinar-like structure formation. TIMP-1 induces expression of the developmental EMT transcription factors such as SLUG

    TWIST

    ZEB1 and ZEB2

    leading to downregulation of epithelial marker and upregulation of mesenchymal markers. Importantly

    TIMP-1's ability to induce the EMT-like process is independent of its MMP-inhibitory domain. To our surprise

    TIMP-1 induces migratory and invasive properties in MDCK cells. Here

    we present a novel finding that TIMP-1 signaling upregulates MT1-MMP and MMP-2 expression

    and potentiates MT1-MMP activation of pro-MMP-2

    contributing to tumor cell invasion. In spite of the fact that TIMP-1

    as opposed to TIMP-2

    does not interact with and inhibit MT1-MMP

    TIMP-1 may act as a key regulator of MT1-MMP/MMP-2 axis. Collectively

    our findings suggest a model in which TIMP-1 functions as a signaling molecule and also as an endogenous inhibitor of MMPs. This concept represents a paradigm shift in the current view of TIMP-1/MT1-MMP interactions and functions during cancer development/progression.

    TIMP-1 induces an EMT-like phenotypic conversion in MDCK cells independent of its MMP-inhibitory domain.

    Abstract\nCertain farnesyl diphosphate (FPP) analogs are potent inhibitors of the potential anticancer drug target protein farnesyltransferase (FTase)

    but these compounds are not suitable as drug candidates. Thus

    phosphoramidate prodrug derivatives of the monophosphate precursors of FPP-based FTase inhibitors have been synthesized. The monophosphates themselves were significantly more potent inhibitors of FTase than the corresponding FPP analogs. The effects of the prodrug 5b (a derivative of 3-allylfarnesyl monophosphate) have been evaluated on prenylation of RhoB and on the cell cycle in a human malignant schwannoma cell line (STS-26T). In combination treatments

    1-3 microM 5b plus 1 microM lovastatin induced a significant inhibition of RhoB prenylation

    and a combination of these drugs at 1 microM each also resulted in significant cell cycle arrest in G1. Indeed

    combinations as low as 50 nM lovastatin + 1 microM 5c or 250 nM lovastatin + 50 nM 5c were highly cytostatic in STS-26T cell culture.

    Synthesis

    biochemical

    and cellular evaluation of farnesyl monophosphate prodrugs as farnesyltransferase inhibitors.

    Abstract\nSomatic mutations or deletions of TP53 and PTEN in ductal carcinoma in situ lesions have been implicated in progression to invasive ductal carcinomas. A recent molecular and mutational analysis of breast cancers revealed that inactivation of tumor suppressors

    p53 and PTEN

    are strongly associated with triple negative breast cancer. In addition

    these tumor suppressors have important roles in regulating self-renewal in normal and malignant stem cells. To investigate their role in breast carcinogenesis

    we knocked down these genes in human mammary cells and in non-transformed MCF10A cells. p53 and PTEN knockdown synergized to activate pro-inflammatory interleukin-6 (IL6)/Stat3/nuclear factor κB signaling. This resulted in generation of highly metastatic epithelial-to-mesenchymal transition-like cancer stem cells resulting in tumors whose gene expression profile mimicked that found in basal/claudin-low molecular subtype within the triple negative breast tumors. Constitutive activation of this loop in transformed cells was dependent on proteolytic degradation of suppressor of cytokine signaling 3 (SOCS3) resulting in low levels of this protein in basal/claudin-low cell lines and primary tumors. In non-transformed cells

    transient activation of the IL6 inflammatory loop induced SOCS3 expression leading to pathway inactivation. In transformed cells

    enforced expression of SOCS3 or interfering with IL6 pathway via IL6R blockade inhibited tumor growth and metastasis in mouse xenograft models. Furthermore

    circulating tumor cells were significantly reduced in tumor-bearing animals when treated with anti-IL6R antibodies. These studies uncover important connections between inflammation and carcinogenesis and suggest that blocking pro-inflammatory cytokines may be utilized as an attractive strategy to target triple negative breast tumors

    which currently lacks molecularly targeted therapies.

    SOCS3-mediated regulation of inflammatory cytokines in PTEN and p53 inactivated triple negative breast cancer model.

    Development of Community-Engaged Research Training Course: Connecting Students

    Faculty

    and Community

    Abstract\nTissue inhibitors of metalloproteinases (TIMPs) are endogenous inhibitors of matrix metalloproteinases (MMPs) and the balance between MMPs/TIMPs regulates the extracellular matrix (ECM) turnover and remodeling during normal development and pathogenesis. Increasing evidence indicates a much more complex role for TIMPs during tumor progression and angiogenesis

    in addition to their regulation of MMP-mediated ECM degradation. In this article

    we review both the MMP-dependent and -independent actions of TIMPs for the regulation of cell death

    cell proliferation

    and angiogenesis

    with a particular emphasis on TIMP-1 in the regulation of tetraspanin/integrin-mediated cell survival signal transduction pathways.\n\nPMID: 16680576 DOI: 10.1007/s10555-006-7893-x

    Novel functions of TIMPs in cell signaling.

    Abstract\nAlthough inactivation of the PTEN gene has been implicated in the development of resistance to the HER2 targeting antibody trastuzumab

    the mechanisms mediating this resistance remain elusive. We generated trastuzumab resistant cells by knocking down PTEN expression in HER2 overexpressing breast cancer cell lines and demonstrate that development of trastuzumab resistance in these cells is mediated by activation of an IL6 inflammatory feedback loop leading to expansion of the cancer stem cell (CSC) population. Long term trastuzumab treatment generates highly enriched CSCs which display an EMT phenotype secreting over 100-fold more IL6 than parental cells. An IL6 receptor antibody interrupted this inflammatory feedback loop reducing the cancer stem cell population resulting in decreased tumor growth and metastasis in mouse xenographs. These studies demonstrate that trastuzumab resistance may be mediated by an IL6 inflammatory loop and suggest that blocking this loop may provide alternative strategy to overcome trastuzumab resistance.\n\n

    Activation of an IL6 inflammatory loop mediates trastuzumab resistance in HER2+ breast cancer by expanding the cancer stem cell population.

    Poster presentation and demonstration of concept mapping for Nutrient Metabolism

    Mapping Out Cellular Respiration

    TIMP-1 induces an epithelial mesenchymal transition via upregulation of the transcription factor Twist in human breast epithelial cells.

    Poster Presentation

    Gordon Research Conference on Basement Membranes

    Barga

    Italy

    June 18-23

    2006\n\n

    TIMP-1 regulation of tetraspanin/integrin survival signaling pathways affecting apoptosis

    cell-cell adhesion

    morphology and polarity of breast epithelial cells.

    Stem cells in normal development and cancer.

    Abstract\nIn this chapter we provide an overview of stem cells in normal tissues as well as in many different types of cancers. All tissues in the body are derived from organ-specific stem cells that retain the ability to self-renew and differentiate into specific cell types. The cancer stem cell hypothesis suggests that tumors arise from cell populations with dysregulated self-renewal. This may be tissue stem cells or more differentiated cells that acquire self-renewal capabilities. In addition

    we outline some useful assays for purification and isolation of cancer stem cells including the dye exclusion side population assay

    flow cytometry sorting techniques for identification of putative cancer stem cell markers

    tumorspheres assay

    aldehyde dehydrogenase activity assay

    PKH

    and other membrane staining used to label the cancer stem cells

    as well as in vivo xenograft transplantation assays. We also examine some of the cell signaling pathways that regulate stem cell self-renewal including the Notch

    Hedgehog

    HER2/PI3K/Akt/PTEN

    and p53 pathways. We also review information demonstrating the involvement of the microenvironment or stem cell niche and its effects on the growth and maintenance of cancer stem cells. Finally

    we highlight the therapeutic implications of targeting stem cells by inhibiting these pathways for the treatment and prevention of cancer.

    Stem cells in normal development and cancer.

    Abstract\nTissue inhibitor of metalloproteinase-1 (TIMP-1) regulates intracellular signaling networks for inhibition of apoptosis. Tetraspanin (CD63)

    a cell surface binding partner for TIMP-1

    was previously shown to regulate integrin-mediated survival pathways in the human breast epithelial cell line MCF10A. In the current study

    we show that TIMP-1 expression induces phenotypic changes in cell morphology

    cell adhesion

    cytoskeletal remodeling

    and motility

    indicative of an epithelial-mesenchymal transition (EMT). This is evidenced by loss of the epithelial cell adhesion molecule E-cadherin with an increase in the mesenchymal markers vimentin

    N-cadherin

    and fibronectin. Signaling through TIMP-1

    but not TIMP-2

    induces the expression of TWIST1

    an important EMT transcription factor known to suppress E-cadherin transcription

    in a CD63-dependent manner. RNAi-mediated knockdown of TWIST1 rescued E-cadherin expression in TIMP-1-overexpressing cells

    demonstrating a functional significance of TWIST1 in TIMP-1-mediated EMT. Furthermore

    analysis of TIMP-1 structural mutants reveals that TIMP-1 interactions with CD63 that activate cell survival signaling and EMT do not require the matrix metalloproteinase (MMP)-inhibitory domain of TIMP-1. Taken together

    these data demonstrate that TIMP-1 binding to CD63 activates intracellular signal transduction pathways

    resulting in EMT-like changes in breast epithelial cells

    independent of its MMP-inhibitory function.\n\nIMPLICATIONS:\nTIMP-1's function as an endogenous inhibitor of MMP or as a \"cytokine-like\" signaling molecule may be a critical determinant for tumor cell behavior.

    TIMP-1 via TWIST1 Induces EMT Phenotypes in Human Breast Epithelial Cells

    Developmental pathways such as notch play a pivotal role in tissue-specific stem cell self-renewal as well as in tumor development. however

    the role of notch signaling in breast cancer stem cells (csc) remains to be determined. we utilized a lentiviral notch reporter system to identify a subset of cells with a higher notch activity (notch(+)) or reduced activity (notch(-)) in multiple breast cancer cell lines. using in vitro and mouse xenotransplantation assays

    we investigated the role of the notch pathway in breast csc regulation. breast cancer cells with increased notch activity displayed increased sphere formation as well as expression of breast csc markers. interestingly notch(+) cells displayed higher notch4 expression in both basal and luminal breast cancer cell lines. moreover

    notch(+) cells demonstrated tumor initiation capacity at serial dilutions in mouse xenografts

    whereas notch(-) cells failed to generate tumors. γ-secretase inhibitor (gsi)

    a notch blocker but not a chemotherapeutic agent

    effectively targets these notch(+) cells in vitro and in mouse xenografts. furthermore

    elevated notch4 and hey1 expression in primary patient samples correlated with poor patient survival. our study revealed a molecular mechanism for the role of notch-mediated regulation of breast cscs and provided a compelling rationale for csc-targeted therapeutics. mol cancer ther; 14(3); 779-87. ©2015 aacr.

    Notch reporter activity in breast cancer cell lines identifies a subset of cells with stem cell activity.

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