Designer monotransregulators provide a basis for a transcriptional therapy for de novo endocrine-resistant breast cancer.

Published

Journal Article

The main circulating estrogen hormone 17beta-estradiol (E2) contributes to the initiation and progression of breast cancer. Estrogen receptors (ERs), as transcription factors, mediate the effects of E2. Ablation of the circulating E2 and/or prevention of ER functions constitute approaches for ER-positive breast cancer treatments. These modalities are, however, ineffective in de novo endocrine-resistant breast neoplasms that do not express ERs. The interaction of E2-ERs with specific DNA sequences, estrogen responsive elements (EREs), of genes constitutes one genomic pathway necessary for cellular alterations. We herein tested the prediction that specific regulation of ERE-driven genes by an engineered monomeric and constitutively active transcription factor, monotransregulator, provides a basis for the treatment of ER-negative breast cancer. Using adenovirus infected ER-negative MDA-MB-231 cells derived from a breast adenocarcinoma, we found that the monotransregulator, but not the ERE-binding defective counterpart, repressed cellular proliferation and motility, and induced apoptosis through expression of genes that required ERE interactions. Similarly, the monotransregulator suppressed the growth of ER-negative BT-549 cells derived from a breast-ductal carcinoma. Moreover, the ERE-binding monotransregulator repressed xenograft tumor growth in a nude mice model. Thus, specific regulation of genes bearing EREs could offer a therapeutic approach for de novo endocrine-resistant breast cancers.

Full Text

Duke Authors

Cited Authors

  • Nott, SL; Huang, Y; Kalkanoglu, A; Harper, K; Chen, M; Paoni, SF; Fenton, BM; Muyan, M

Published Date

  • January 2010

Published In

Volume / Issue

  • 16 / 1-2

Start / End Page

  • 10 - 18

PubMed ID

  • 19946606

Pubmed Central ID

  • 19946606

Electronic International Standard Serial Number (EISSN)

  • 1528-3658

Digital Object Identifier (DOI)

  • 10.2119/molmed.2009.00107

Language

  • eng

Conference Location

  • England