Abstract

Transforming growth factor-beta (TGF-beta) is a potent inhibitor of human mammary epithelial proliferation. During mammary carcinogenesis most breast cancer cells become resistant to the growth inhibitory effects of TGF-beta; TGF-beta then promotes breast cancer tumor formation. Fundamental gaps in knowledge exist in terms of the mechanisms (1) by which breast cancers become TGF-beta resistant and (2) by which TGF-beta functions as both a tumor suppressor and a tumor promoter during mammary carcinogenesis. The type III TGF-beta receptor (TbetaRIII) has an emerging yet poorly understood role in regulating TGF-beta signaling and mammary carcinogenesis. Based on preliminary studies establishing the scaffolding protein beta-arrestin2 as a TbetaRlII-interacting protein, the following hypothesis is proposed: Interaction of TbetaRIII with beta-arrestin2 during mammmary carcinogenesis mediates (1) the internalization and downregulation of TGF-beta receptors, resulting in resistance to TGF-beta-mediated inhibition of proliferation and (2) stimulation of TbetaRIII-dependent signaling to MAP kinase pathways promoting tumor formation. This hypothesis will be addressed by four Specific Aims.
Specific Aim 1 : The TbetaRIII/beta-arrestin2 interaction will be characterized and the effects of TbetaRIII phosphorylation and TbetaRIII-interacting proteins (GIPC, TbetaRII) on the TbetaRIII/beta arrestin2 interaction and beta-arrestin2-mediated TbetaRIII internalization in human breast cancer cells will be established.
Specific Aim 2 : The effect of beta-arrestin2 on TbetaRIII expression, downregulation, TGF-beta signaling and TGF-beta-mediated inhibition of proliferation in human breast cancer cells will be established to define whether TbetaRIII/beta-arrestin2 mediates the tumor suppressor effects of TGF-beta during mammary carcinogenesis.
Specific Aim 3 : The effect of beta-arrestin2 on TbetaRIII-dependent signaling to MAP kinase pathways and on the proliferation, motility, survival and anchorage-independent growth of human breast cancer cells will be established to define whether TbetaRIIl/beta-arrestin2 mediates the tumor promoting effects of TGF-beta during mammary carcinogenesis.
Specific Aim 4 : The effect of altering beta-arrestin2 or GIPC expression or the ability of TbetaRIII to interact with beta-arrestin2 or GIPC on the balance of TbetaRIII-mediated Smad-dependent and Smad-independent signaling and on the tumorigenicity/metastatic potential of breast cancer cells in vivo will be established to determine whether TbetaRIII through beta-arrestin2 regulates TGF-beta signaling during mammary carcinogenesis. These studies will define mechanisms for TGF-beta-resistance, for Smad-independent signaling and for the dichotomous role of TGF-beta in mammary carcinogenesis and aid in targeting the TGF-beta signaling pathway for the chemoprevention and treatment of human breast cancers and other human cancers in which TGF-beta has a defined role.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA106307-04
Application #
7413596
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Salnikow, Konstantin
Project Start
2005-07-01
Project End
2010-04-30
Budget Start
2008-05-01
Budget End
2009-04-30
Support Year
4
Fiscal Year
2008
Total Cost
$288,390
Indirect Cost

  Institution

Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705

  Publications

Huang, Jennifer J; Blobe, Gerard C (2016) Dichotomous roles of TGF-? in human cancer. Biochem Soc Trans 44:1441-1454
Lee, Jason D; Hempel, Nadine; Lee, Nam Y et al. (2010) The type III TGF-beta receptor suppresses breast cancer progression through GIPC-mediated inhibition of TGF-beta signaling. Carcinogenesis 31:175-83
Cooper, S J; Zou, H; Legrand, S N et al. (2010) Loss of type III transforming growth factor-beta receptor expression is due to methylation silencing of the transcription factor GATA3 in renal cell carcinoma. Oncogene 29:2905-15
You, Hye Jin; How, Tam; Blobe, Gerard C (2009) The type III transforming growth factor-beta receptor negatively regulates nuclear factor kappa B signaling through its interaction with beta-arrestin2. Carcinogenesis 30:1281-7
Mythreye, Karthikeyan; Blobe, Gerard C (2009) The type III TGF-beta receptor regulates epithelial and cancer cell migration through beta-arrestin2-mediated activation of Cdc42. Proc Natl Acad Sci U S A 106:8221-6
Mythreye, Karthikeyan; Blobe, Gerard C (2009) Proteoglycan signaling co-receptors: roles in cell adhesion, migration and invasion. Cell Signal 21:1548-58
Lee, Nam Y; Kirkbride, Kellye C; Sheu, Richard D et al. (2009) The transforming growth factor-beta type III receptor mediates distinct subcellular trafficking and downstream signaling of activin-like kinase (ALK)3 and ALK6 receptors. Mol Biol Cell 20:4362-70
Gordon, Kelly J; Kirkbride, Kellye C; How, Tam et al. (2009) Bone morphogenetic proteins induce pancreatic cancer cell invasiveness through a Smad1-dependent mechanism that involves matrix metalloproteinase-2. Carcinogenesis 30:238-48
Hempel, Nadine; How, Tam; Cooper, Simon J et al. (2008) Expression of the type III TGF-beta receptor is negatively regulated by TGF-beta. Carcinogenesis 29:905-12
Finger, Elizabeth C; Lee, Nam Y; You, Hye-jin et al. (2008) Endocytosis of the type III transforming growth factor-beta (TGF-beta) receptor through the clathrin-independent/lipid raft pathway regulates TGF-beta signaling and receptor down-regulation. J Biol Chem 283:34808-18

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