Regulation of aromatase induction by nuclear receptor coregulator PELP1

Ratna K. Vadlamudi, Rajib Rajhans, Dimple Chakravarty, Binoj C. Nair, Sujit S. Nair, Dean B. Evans, Shiuan Chen, Rajeshwar Rao Tekmal

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Estradiol (E2), estrogen receptor (ER), ER-coregulators have been implicated in the development and progression of breast cancer. In situ E2 synthesis is implicated in tumor cell proliferation through autocrine or paracrine mechanisms, especially in post-menopausal women. Several recent studies demonstrated activity of aromatase P450 (Cyp19), a key enzyme that plays critical role in E2 synthesis in breast tumors. The mechanism by which tumors enhance aromatase expression is not completely understood. Recent studies from our laboratory suggested that PELP1 (Proline, Glutamic acid, Leucine rich Protein 1), a novel ER-coregulator, functions as a potential proto-oncogene and promotes tumor growth in nude mice models without exogenous E2 supplementation. In this study,wefound that PELP1 deregulation contributes to increased expression of aromatase, local E2 synthesis and PELP1 cooperates with growth factor signaling components in the activation of aromatase. PELP1 deregulation uniquely up-regulated aromatase expression via activation of aromatase promoter I.3/II. Analysis of PELP1 drivenmammarytumors in xenograft as well as in transgenic mouse models revealed increased aromatase expression. PELP1-mediated induction of aromatase requires functional Src and PI3K pathways. Chromatin immuno precipitation (ChIP) assays revealed that PELP1 is recruited to the Aro 1.3/II aromatase promoter. HER2 signaling enhances PELP1 recruitment to the aromatase promoter and PELP1 plays a critical role in HER2-mediated induction of aromatase expression. Mechanistic studies revealed that PELP1 interactions with orphan receptor ERRα, and histone demethylases play a role in the activation of aromatase promoter. Accordingly, ChIP analysis showed alterations in histone modifications at the aromatase promoter in the model cells that exhibit local E2 synthesis. Immunohistochemical analysis of breast tumor progression tissue arrays suggested that deregulation of aromatase expression occurs in advanced-stage and node-positive tumors, and that cooverexpression of PELP1 and aromatase occur in a sub set of tumors. Collectively, our results suggest that PELP1 regulation of aromatase represent a novel mechanism for in situ estrogen synthesis leading to tumor proliferation by autocrine loop and open a new avenue for ablating local aromatase activity in breast tumors.

Original languageEnglish (US)
Pages (from-to)211-218
Number of pages8
JournalJournal of Steroid Biochemistry and Molecular Biology
Volume118
Issue number4-5
DOIs
StatePublished - Feb 28 2010

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Keywords

  • Aromatase
  • Breast cancer
  • Coregulators
  • ERRα
  • Epigenetics
  • Estrogen
  • Estrogen receptor
  • PELP1

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Endocrinology
  • Clinical Biochemistry
  • Cell Biology

Cite this

Vadlamudi, R. K., Rajhans, R., Chakravarty, D., Nair, B. C., Nair, S. S., Evans, D. B., Chen, S., & Tekmal, R. R. (2010). Regulation of aromatase induction by nuclear receptor coregulator PELP1. Journal of Steroid Biochemistry and Molecular Biology, 118(4-5), 211-218. https://doi.org/10.1016/j.jsbmb.2009.09.009