Antiestrogen-resistant subclones of MCF-7 human breast cancer cells are derived from a common monoclonal drug-resistant progenitor

• Published in: Proceedings of the National Academy of Sciences - PNAS 2009-08, Vol.106 (34), p.14536-14541
• Main Authors: Coser, Kathryn R, Wittner, Ben S, Rosenthal, Noël F, Collins, Sabrina C, Melas, Antonia, Smith, Shannon L, Mahoney, Crystal J, Shioda, Keiko, Isselbacher, Kurt J, Ramaswamy, Sridhar, Shioda, Toshi
• Format: Article
• Language: English
• Subjects: Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Biological Sciences; Blotting, Western; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell culture techniques; Cell Cycle - drug effects; Cell Line, Tumor; Cell lines; Cell Survival - drug effects; Chromosome Mapping; Clone Cells - drug effects; Clone Cells - metabolism; Deoxyribonucleic acid; DNA; Drug resistance; Drug Resistance, Neoplasm - genetics; Estradiol - analogs & derivatives; Estradiol - pharmacology; Estrogen Receptor alpha - genetics; Estrogen Receptor alpha - metabolism; Estrogen Receptor Modulators - pharmacology; Estrogens; Female; Flow Cytometry; Gene Expression Profiling; Gene Expression Regulation, Neoplastic - drug effects; Gene Regulatory Networks; Genes; Genetic heterogeneity; Genome-Wide Association Study - methods; Genomics; Humans; Membrane Proteins - genetics; Membrane Proteins - metabolism; Oligonucleotide Array Sequence Analysis; Progenitor cells; Signatures; Stem cells; Tamoxifen - pharmacology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0907560106

Emergence of antiestrogen-resistant cells in MCF-7 cells during suppression of estrogen signaling is a widely accepted model of acquired breast cancer resistance to endocrine therapy. To obtain insight into the genomic basis of endocrine therapy resistance, we characterized MCF-7 monoclonal sublines that survived 21-day exposure to tamoxifen (T-series sublines) or fulvestrant (F-series sublines) and sublines unselected by drugs (U-series). All T/F-sublines were resistant to the cytocidal effects of both tamoxifen and fulvestrant. However, their responses to the cytostatic effects of fulvestrant varied greatly, and their remarkably diversified morphology showed no correlation with drug resistance. mRNA expression profiles of the U-sublines differed significantly from those of the T/F-sublines, whose transcriptomal responsiveness to fulvestrant was largely lost. A set of genes strongly expressed in the U-sublines successfully predicted metastasis-free survival of breast cancer patients. Most T/F-sublines shared highly homogeneous genomic DNA aberration patterns that were distinct from those of the U-sublines. Genomic DNA of the U-sublines harbored many aberrations that were not found in the T/F-sublines. These results suggest that the T/F-sublines are derived from a common monoclonal progenitor that lost transcriptomal responsiveness to antiestrogens as a consequence of genetic abnormalities many population doublings ago, not from the antiestrogen-sensitive cells in the same culture during the exposure to antiestrogens. Thus, the apparent acquisition of antiestrogen resistance by MCF-7 cells reflects selection of preexisting drug-resistant subpopulations without involving changes in individual cells. Our results suggest the importance of clonal selection in endocrine therapy resistance of breast cancer.