A genome-wide study of the repressive effects of estrogen receptor beta on estrogen receptor alpha signaling in breast cancer cells

• Published in: Oncogene Vol. 27; no. 7; pp. 1019 - 1032
• Main Authors: Williams, C, Edvardsson, K, Lewandowski, S A, Ström, A, Gustafsson, J-Å
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07-02-2008; Nature Publishing; Nature Publishing Group
• Subjects: Angiogenesis; Apoptosis; Biological and medical sciences; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Care and treatment; Cell Biology; Cell Line, Tumor; Cell physiology; Cell Proliferation; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Estradiol - pharmacology; Estrogen; Estrogen Receptor alpha - antagonists & inhibitors; Estrogen Receptor alpha - genetics; Estrogen Receptor alpha - metabolism; Estrogen Receptor beta - genetics; Estrogen Receptor beta - metabolism; Estrogen receptors; Estrogens; Estrogens - pharmacology; Female; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Neoplastic; Gene regulation; Genetic aspects; Genetic transcription; Genome, Human; Genomes; Genomics; Gynecology. Andrology. Obstetrics; Health aspects; Human Genetics; Humans; Internal Medicine; Isoforms; Mammary gland diseases; Medical sciences; Medicin och hälsovetenskap; Medicine; Medicine & Public Health; Molecular and cellular biology; Oligonucleotide Array Sequence Analysis; oncogenomics; Oncology; Receptors; Reverse Transcriptase Polymerase Chain Reaction; RNA, Neoplasm - genetics; RNA, Neoplasm - metabolism; Signal Transduction; SRA - Molecular Bioscience; SRA - Molekylär biovetenskap; Transcription; Transcription, Genetic; Transcriptomes; Tumors; Xenografts; Sweden; breast cancer; microarray; estrogen receptor; gene regulation; Mammary gland diseases; Estrogen receptor; Regulation(control); Breast disease; Gene; Breast cancer; Malignant tumor; Microarray; Carcinogenesis; Cancer
• ISSN: 0950-9232; 1476-5594; 1476-5594
• DOI: 10.1038/sj.onc.1210712

Transcriptional effects of estrogen result from its activation of two estrogen receptor (ER) isoforms; ER
α
that drives proliferation and ER
β
that is antiproliferative. Expression of ER
β
in xenograft tumors from the T47D breast cancer cell line reduces tumor growth and angiogenesis. If ER
β
can halt tumor growth, its introduction into cancers may be a novel therapeutic approach to the treatment of estrogen-responsive cancers. To assess the complete impact of ER
β
on transcription, we have made a full transcriptome analysis of ER
α
- and ER
β
-mediated gene regulation in T47D cell line with Tet-Off regulated ER
β
expression. Of the 35 000 genes and transcripts analysed, 4.1% (1434) were altered by ER
α
activation. Tet withdrawal and subsequent ER
β
expression inhibited the ER
α
regulation of 998 genes and, in addition, altered expression of 152 non-ER
α
-regulated genes. ER
α
-induced and ER
β
-repressed genes were involved in proliferation, steroid/xenobiotic metabolism and ion transport. The ER
β
repressive effect was further confirmed by proliferation assays, where ER
β
was shown to completely oppose the ER
α
–E2 induced proliferation. Additional analysis of ER
β
with a mutated DNA-binding domain revealed that this mutant, at least for a quantity of genes, antagonizes ER
α
even more strongly than ER
β
wt. From an examination of the genes regulated by ER
α
and ER
β
, we suggest that introduction of ER
β
may be an alternative therapeutic approach to the treatment of certain cancers.