AUTOCRINE TGF B AND BREAST CANCER CELL GROWTH

  • Brattain, Michael G, (PI)

Project: Research project

Description

DESCRIPTION: The loss of TGFB type II receptor (TGFRII) expression is an important determinant in malignancy of ER+ breast cancer cells which generally express deficient levels of receptor. The applicant has shown re-expression of TGFRII in MCF-7 cells leading to reduced tumorigenicity. Response to vitamin D3 analogues (VD3) segregates with inducibility of TGFRII expression and negative autocrine growth control. VD3 leads to increased levels of p21 and p27 cyclin dependent kinase inhibitors. Elucidation of the controls of TGFRII expression may lead to key targets for increasing TGFB negative growth regulation and thus, VD3 effects on therapy and/or prevention. The first objective is to determine the mechanism of cell cycle growth arrest by VD3 analogues. The applicant hypothesizes that p21 and p27 are central elements in the VD3 growth arrest mechanism and that regeneration of TGFB activity leads to increased inhibitor expression. The importance of the lack of TGFRII expression in malignancy underlies the need for understanding the epigenetic mechanisms responsible for its repression in ER+ cells is the second objective. The applicant hypothesizes and provide preliminary data that repression of TGFRII is associated with ER function resulting in DNA methylation. The third objective is to determine how VD3 analogues increase TGFRII transcription. The specific aims to address these aspects of the interaction of VD3, expression of TGFRII and cell cycle arrest are to: 1) determine the role of the p21 and p27 CDK inhibitors in cell cycle arrest by VD3 analogues; 2) determine the effects of anti-estrogen treatment on TGFRII expression; 3) determine the mechanism by which methylation represses TGFRII expression; 4) determine the mechanism by which VD3 analogues induce TGFRII expression.
StatusFinished
Effective start/end date6/1/977/31/12

Funding

  • National Institutes of Health
  • National Institutes of Health: $241,433.00
  • National Institutes of Health: $280,239.00
  • National Institutes of Health: $248,900.00
  • National Institutes of Health: $182,088.00
  • National Institutes of Health: $177,425.00
  • National Institutes of Health: $248,900.00
  • National Institutes of Health: $248,900.00
  • National Institutes of Health: $283,674.00
  • National Institutes of Health
  • National Institutes of Health: $248,900.00
  • National Institutes of Health: $270,544.00
  • National Institutes of Health: $273,681.00
  • National Institutes of Health: $276,912.00

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Transforming Growth Factor beta
Breast Neoplasms
Cholecalciferol
Histone Deacetylase Inhibitors
Growth
Cell Death
Tumor Suppressor Genes
Regeneration
Neoplasms
Heterografts
Apoptosis
Cell Cycle Checkpoints
Cyclin-Dependent Kinase Inhibitor p27
Colonic Neoplasms
Transcription Factors
Transfection
MCF-7 Cells
Deoxycytidine
Breast
Epithelial Cells

ASJC

  • Medicine(all)