Designer monotransregulators provide a basis for a transcriptional therapy for de novo endocrine-resistant breast cancer.
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.
Nott
Stephanie L
SL
Department of Biochemistry and Biophysics, University of Rochester Medical School, Rochester, New York, United States of America.
Huang
Yanfang
Y
Kalkanoglu
Aja
A
Harper
Kathryn
K
Chen
Ming
M
Paoni
Scott F
SF
Fenton
Bruce M
BM
Muyan
Mesut
M
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D016923:Cell Death / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D004958:Estradiol / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005809:Genes, Regulator; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D020218:Response Elements; D023041:Xenograft Model Antitumor Assays
D047628:Estrogen Receptor alpha; D004958:Estradiol