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 hav...

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Bibliographic Details
Published in:Breast cancer research and treatment 2011-07, Vol.128 (2), p.357-368
Main Authors: Tolhurst, Robert S., Thomas, Ross S., Kyle, Fiona J., Patel, Hetal, Periyasamy, Manikandan, Photiou, Andrew, Thiruchelvam, Paul T. R., Lai, Chun-Fui, Al-sabbagh, Marwa, Fisher, Rosemary A., Barry, Sayka, Crnogorac-Jurcevic, Tatjana, Martin, Lesley-Ann, Dowsett, Mitch, Charles Coombes, R., Kamalati, Tahereh, Ali, Simak, Buluwela, Laki
Format: Article
Language:English
Subjects:
Adenoviridae - genetics
Analysis
Antineoplastic Agents, Hormonal - therapeutic use
Apoptosis
Biological and medical sciences
Biomarkers, Tumor - genetics
Biomarkers, Tumor - metabolism
Blotting, Western
Breast cancer
Breast Neoplasms - genetics
Breast Neoplasms - metabolism
Breast Neoplasms - pathology
Cancer cells
Cell Cycle
Cell Proliferation
DNA microarrays
Drug Resistance, Neoplasm
Estrogen
Estrogen Receptor alpha - genetics
Estrogen Receptor alpha - metabolism
Estrogens - pharmacology
Etoposide
Female
Gene expression
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Genes
Growth
Gynecology. Andrology. Obstetrics
Health aspects
Humans
Mammary gland diseases
Medical sciences
Medicine
Medicine & Public Health
Oligonucleotide Array Sequence Analysis
Oncology
Phenols
Physiological aspects
Preclinical Study
Reverse Transcriptase Polymerase Chain Reaction
RNA, Messenger - genetics
Tamoxifen
Tamoxifen - therapeutic use
Toy industry
Tumor Cells, Cultured
Tumors
Video game industry
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Summary: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.
ISSN:0167-6806
1573-7217
DOI:10.1007/s10549-010-1122-6