Genome-Wide Analysis of Aromatase Inhibitor-Resistant, Tamoxifen-Resistant, and Long-Term Estrogen-Deprived Cells Reveals a Role for Estrogen Receptor
Open Access
- 15 June 2008
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 68 (12), 4910-4918
- https://doi.org/10.1158/0008-5472.can-08-0303
Abstract
Acquired resistance to either tamoxifen or aromatase inhibitors (AI) develops after prolonged treatment in a majority of hormone-responsive breast cancers. In an attempt to further elucidate mechanisms of acquired resistance to AIs, MCF-7aro cells resistant to letrozole (T+LET R), anastrozole (T+ANA R), and exemestane (T+EXE R), as well as long-term estrogen deprived (LTEDaro) and tamoxifen-resistant (T+TAM R) lines were generated. This is the first complete panel of endocrine therapy–resistant cell lines, which were generated as multiple independent biological replicates for unbiased genome-wide analysis using affymetrix microarrays. Although similarities are apparent, microarray results clearly show gene signatures unique to AI-resistance were inherently different from LTEDaro and T+TAM R gene expression profiles. Based on hierarchical clustering, unique estrogen-responsive gene signatures vary depending on cell line, with some genes up-regulated in all lines versus other genes up-regulated only in the AI-resistant lines. Characterization of these resistant lines showed that LTEDaro, T+LET R, and T+ANA R cells contained a constitutively active estrogen receptor (ER)α that does not require estrogen for activation. This ligand-independent activation of ER was not observed in the parental cells, as well as T+EXE R and T+TAM R cells. Further characterization of these resistant lines was performed using cell cycle analysis, immunofluorescence experiments to visualize ER subcellular localization, as well as cross-resistance studies to determine second-line inhibitor response. Using this well-defined model system, our studies provide important information regarding differences in resistance mechanisms to AIs, TAM, and LTEDaro, which are critical in overcoming resistance when treating hormone-responsive breast cancers. [Cancer Res 2008;68(12):4910–8]Keywords
Other Versions
This publication has 41 references indexed in Scilit:
- The Role of Amphiregulin in Exemestane-Resistant Breast Cancer Cells: Evidence of an Autocrine LoopCancer Research, 2008
- Molecular response to aromatase inhibitor treatment in primary breast cancerBreast Cancer Research, 2007
- What do we know about the mechanisms of aromatase inhibitor resistance?The Journal of Steroid Biochemistry and Molecular Biology, 2006
- Endocrine therapy resistance can be associated with high estrogen receptor α (ERα) expression and reduced ERα phosphorylation in breast cancer modelsEndocrine-Related Cancer, 2006
- Estrogen Carcinogenesis in Breast CancerNew England Journal of Medicine, 2006
- Elevated Src activity promotes cellular invasion and motility in tamoxifen resistant breast cancer cellsBreast Cancer Research and Treatment, 2005
- Bidirectional cross talk between ERα and EGFR signalling pathways regulates tamoxifen-resistant growthBreast Cancer Research and Treatment, 2005
- The Role of Growth Factor Receptor Pathways in Human Breast Cancer Cells Adapted to Long-term Estrogen DeprivationCancer Research, 2005
- A Randomized Trial of Exemestane after Two to Three Years of Tamoxifen Therapy in Postmenopausal Women with Primary Breast CancerNew England Journal of Medicine, 2004
- A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye bindingAnalytical Biochemistry, 1976