Inhibitory effects of estrogen receptor beta on specific hormone-responsive gene expression and association with disease outcome in primary breast cancer.
BACKGROUND
The impact of interactions between the two estrogen receptor (ER) subtypes, ERalpha and ERbeta, on gene expression in breast cancer biology is not clear. The goal of this study was to examine transcriptomic alterations in cancer cells co-expressing both receptors and the association of gene expression signatures with disease outcome.


METHODS
Transcriptional effects of ERbeta overexpression were determined in a stably transfected cell line derived from ERalpha-positive T-47D cells. Microarray analysis was carried out to identify differential gene expression in the cell line, and expression of key genes was validated by quantitative polymerase chain reaction. Microarray and clinical data from patient samples were then assessed to determine the in vivo relevance of the expression profiles observed in the cell line.


RESULTS
A subset of 14 DNA replication and cell cycle-related genes was found to be specifically downregulated by ERbeta. Expression profiles of four genes, CDC2, CDC6, CKS2, and DNA2L, were significantly inversely correlated with ERbeta transcript levels in patient samples, consistent with in vitro observations. Kaplan-Meier analysis revealed better disease outcome for the patient group with an expression signature linked to higher ERbeta expression as compared to the lower ERbeta-expressing group for both disease-free survival (p = 0.00165) and disease-specific survival (p = 0.0268). These findings were further validated in an independent cohort.


CONCLUSIONS
Our findings revealed a transcriptionally regulated mechanism for the previously described growth inhibitory effects of ERbeta in ERalpha-positive breast tumor cells and provide evidence for a functional and beneficial impact of ERbeta in primary breast tumors.
Lin
Chin-Yo
CY
Genome Institute of Singapore, Singapore 138672, Republic of Singapore. chinyolin@byu.edu
Ström
Anders
A
Li Kong
Say
S
Kietz
Silke
S
Thomsen
Jane S
JS
Tee
Jason B S
JB
Vega
Vinsensius B
VB
Miller
Lance D
LD
Smeds
Johanna
J
Bergh
Jonas
J
Gustafsson
Jan-Ake
JA
Liu
Edison T
ET
D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018572:Disease-Free Survival; D050684:E2F Transcription Factors / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000378:metabolism / Q000502:physiology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D005810:Multigene Family; D020411:Oligonucleotide Array Sequence Analysis; D014158:Transcription, Genetic; D014162:Transfection; D016896:Treatment Outcome
D050684:E2F Transcription Factors; D047629:Estrogen Receptor beta