PELP1, a Novel Regulator of Estrogen Receptor

  • Vadlamudi, Ratna K (PI)

Project: Research project

Project Details

Description

DESCRIPTION (provided by applicant): Breast cancer is the leading type of cancer among women. Steroid hormone 17 beta-estradiol (E2) plays an important role in controlling the expression of genes involved in a wide variety of biological processes, including development, homeostasis and breast tumor progression. The biological effects of estrogen are mediated by its binding to estrogen receptor (ER). Approximately 70% of breast cancer cells express ER. Many ER-positive tumors that initially responded to antiestrogens later acquire resistance and exhibit mixed/agonist responses. Recent evidence suggests that the relevant action of estrogen and or antiestrogens in a given cell or tumor depends on the concentration of different coactivators or corepressors that modulate ER activity. In spite of these developments, our understanding of direct cause- and effect relationship between coactivators (as a critical regulators of ER) and ER signaling, and its impact on the pathobiology of breast cancer remains poorly understood. This proposal is intended to establish the role of a newly discovered coactivator (PELP1, see below) in the molecular progression of breast cancer using novel in vitro and in vivo mammary epithelial model systems. Recently, I cloned a novel ER alpha regulatory protein, Proline Glutamic acid and Leucine rich Protein (PELP1), that is abundantly expressed in the mammary gland. PELP1 is novel as it has no homology with existing coactivators, its expression is developmentally regulated in the mammary gland and upregulated ERalpha-driven transcription. In addition, PELP1 interacts with the retinoblastoma protein and promotes its hyperphosphorylation. Furthermore, PELP1 may be over expressed in human breast tumors compared to adjacent paired normal mammary gland tissues. My working hypothesis is that upregulation of PELP1 expression and functions may confer a growth advantage to breast epithelial cells and result in malignant progression by hyperstimulating ER pathway. The overall goals of this proposal are to (1) characterize the molecular events that mediate PELP1 regulation of ER pathways by domain analysis and by creating dominant negative mutants; (2) characterize the molecular mechanism of action of PELP1 by studying the nuclear function of PELP1 including, intrinsic/associated enzymatic activities, chromatin modification, and correlation with coactivation function; (3) characterize the role of PELP1 in cell proliferation by using cell lines expressing PELP1 under an inducible promoter, and studying the role of overexpression on the growth-rate, cell cycle progression and (4) characterize the role of PELP1 in tumorigenesis. The proposed studies will allow us to understand the functions of newly cloned PELP1, its role in ER signaling and provide a molecular explanation for the widely recognized differential responses of estrogen and antiestrogens. This proposal is novel because of the presence of unique structural motifs with diverse cellular functions in PELP1 and the fact that it is upregulated in breast tumors.
StatusFinished
Effective start/end date2/1/021/31/15

Funding

  • National Institutes of Health: $47,647.00
  • National Institutes of Health: $257,887.00
  • National Institutes of Health: $98,003.00
  • National Institutes of Health: $42,360.00
  • National Institutes of Health: $257,887.00
  • National Institutes of Health: $265,341.00
  • National Institutes of Health: $254,540.00
  • National Institutes of Health: $268,780.00
  • National Institutes of Health: $253,773.00
  • National Institutes of Health: $265,863.00
  • National Institutes of Health: $146,000.00
  • National Institutes of Health: $242,413.00
  • National Institutes of Health: $14,240.00
  • National Institutes of Health: $51,499.00
  • National Institutes of Health: $29,296.00
  • National Institutes of Health: $51,387.00

ASJC

  • Medicine(all)

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