Transient over-expression of estrogen receptor-α in breast cancer cells promotes cell survival and estrogen-independent growth.
Estrogen receptor-α (ERα) positive breast cancer frequently responds to inhibitors of ERα activity, such as tamoxifen, and/or to aromatase inhibitors that block estrogen biosynthesis. However, many patients become resistant to these agents through mechanisms that remain unclear. Previous studies have shown that expression of ERα in ERα-negative breast cancer cell lines frequently inhibits their growth. In order to determine the consequence of ERα over-expression in ERα-positive breast cancer cells, we over-expressed ERα in the MCF-7 breast cancer cell line using adenovirus gene transduction. ERα over-expression led to ligand-independent expression of the estrogen-regulated genes pS2 and PR and growth in the absence of estrogen. Interestingly, prolonged culturing of these cells in estrogen-free conditions led to the outgrowth of cells capable of growth in cultures from ERα transduced, but not in control cultures. From these cultures a line, MLET5, was established which remained ERα-positive, but grew in an estrogen-independent manner. Moreover, MLET5 cells were inhibited by anti-estrogens showing that ERα remains important for their growth. Gene expression microarray analysis comparing MCF-7 cells with MLET5 highlighted apoptosis as a major functional grouping that is altered in MLET5 cells, such that cell survival would be favoured. This conclusion was further substantiated by the demonstration that MLET5 show resistance to etoposide-induced apoptosis. As the gene expression microarray analysis also shows that the apoptosis gene set differentially expressed in MLET5 is enriched for estrogen-regulated genes, our findings suggest that transient over-expression of ERα could lead to increased cell survival and the development of estrogen-independent growth, thereby contributing to resistance to endocrine therapies in breast cancer patients.
Tolhurst
Robert S
RS
Division of Cancer, Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
Thomas
Ross S
RS
Kyle
Fiona J
FJ
Patel
Hetal
H
Periyasamy
Manikandan
M
Photiou
Andrew
A
Thiruchelvam
Paul T R
PT
Lai
Chun-Fui
CF
Al-Sabbagh
Marwa
M
Fisher
Rosemary A
RA
Barry
Sayka
S
Crnogorac-Jurcevic
Tatjana
T
Martin
Lesley-Ann
LA
Dowsett
Mitch
M
Charles Coombes
R
R
Kamalati
Tahereh
T
Ali
Simak
S
Buluwela
Laki
L
D000256:Adenoviridae / Q000235:genetics; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002453:Cell Cycle; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013629:Tamoxifen / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D004967:Estrogens; D012333:RNA, Messenger; D013629:Tamoxifen