Mechanisms of Altered Control of Proliferation by Cyclic Amp/Protein Kinase A During Mammary Tumor Progression

Abstract

Changes in signal transduction networks occur during mammary tumor progression that affect the proliferative response of the cells to exogenous factors. These alterations may be related to the loss of hormonal regulation of breast cancer which has a major impact on prognosis and therapy of breast cancer. The goal of this research was to identity the mechanisms underlying the difference in the proliferative response to 3'-5' cyclic adenosine monophosphate (cAMP) that we observed in our rodent model systems (Imagawa et aL 1992). cAMP is a potent mitogen for normal mammary gland epithelium, weakly nitogenic for hormone-dependent mammary tumors and growth inhibitory to hormone-independent mammary tumors. cAMP-stimulated proliferation was inhibited by pertussis toxin (PT) in normal mammary epithelium but neither the inhibitory effect of cAMP nor basal cAMP-independent proliferation of hormone-independent mammary tumors was affected by PT (Imagawa et al. 1995). PT is a bacterial toxin that ADP-ribosylates G(Delta)i(Beta)y subunits and blocks activation of receptor-coupled heterotrimeric G(Delta)i(Beta)y proteins. These findings indicate that through postreceptor crosstalk, pertussis toxin-sensitive Ga i 3y pathways modulate cAMP-mediated proliferation. These preliminary results led to the hypothesis that a critical alteration in growth regulation related to signaling pathways affected by cAMP and pertussis toxin-sensitive G proteins occurs during transformation and progression of mammary tumors from hormone-dependent to hormone-independent growth. Furthermore, these effector pathways could play a pivotal role in coordinating multiple growth-stimulatory pathways and can modulate the hormonal responsiveness of mammary epithelium.

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Document Details

Document Type
Technical Report
Publication Date
Jun 01, 2001
Accession Number
ADA405281

Entities

People

  • Walter Imagawa

Organizations

  • Kansas City University

Tags

DTIC Thesaurus Topics

  • Biological Factors
  • Biomedical And Dental Materials
  • Cell Line
  • Cell Physiological Processes
  • Cells
  • Chemistry
  • Culture Techniques
  • Cultured Cells
  • Epithelial Cells
  • Growth Factors
  • Hormones
  • Inhibition
  • Mammary Glands
  • Peptide Growth Factors
  • Proteins
  • Tissues
  • Tumor Cell Line

Fields of Study

  • Biology

Readers

  • Breast cancer cell signaling and growth regulation.
  • Cellular and Molecular Pathways of Apoptosis.