Research article summary (published 23 Aug 2009):

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

Full Abstract

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.

Author information

Author/s: Coser, Kathryn R (KR); Wittner, Ben S (BS); Rosenthal, Noël F (NF); Collins, Sabrina C (SC); Melas, Antonia (A); Smith, Shannon L (SL); Mahoney, Crystal J (CJ); Shioda, Keiko (K); Isselbacher, Kurt J (KJ); Ramaswamy, Sridhar (S); Shioda, Toshi (T);

Affiliation: Center for Cancer Research, Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA 02129, USA.

Grants: 2P50 CA89393–07 (Agency:NCI NIH HHS)

Journal and publication information

Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.

Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A), published in United States. (Language: eng)

Reference: 2009-Aug; vol 106 (issue 34) : pp 14536-41

Dates: Created 2009/08/26; Completed 2009/09/28;

PMID: 19706540, status: MEDLINE (last retrieval date: 9/28/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Apoptosis Regulatory Proteins - genetics; metabolism Blotting, Western Breast Neoplasms - genetics; metabolism; pathology Cell Cycle - drug effects Cell Line, Tumor Cell Survival - drug effects Chromosome Mapping Clone Cells - drug effects; metabolism Drug Resistance, Neoplasm - genetics Estradiol - analogs & derivatives; pharmacology Estrogen Receptor Modulators - pharmacology

Estrogen Receptor alpha - genetics; metabolism Female Flow Cytometry Gene Expression Profiling Gene Expression Regulation, Neoplastic - drug effects Gene Regulatory Networks Genome-Wide Association Study - methods Humans Membrane Proteins - genetics; metabolism Oligonucleotide Array Sequence Analysis Tamoxifen - pharmacology

Associated Chemicals: Apoptosis Regulatory Proteins (0) ; BIK protein, human (0) ; Estrogen Receptor Modulators (0) ; Estrogen Receptor alpha (0) ; Membrane Proteins (0) ; Tamoxifen (10540-29-1) ; fulvestrant (129453-61-8) ; Estradiol (50-28-2)

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