Genetic events during the transformation of a tamoxifen-sensitive human breast cancer cell line into a drug-resistant clone.
Tamoxifen resistance is a serious clinical problem commonly encountered in the management of patients with breast cancer. The mechanisms leading to its development are unclear. Tamoxifen acts via multiple pathways and has diverse effects. Hence transformation from a tamoxifen-sensitive to a resistant phenotype could involve multiple genetic events. Knowledge of the genetic pathways leading to resistance may facilitate the development of novel therapeutic strategies. In this study, a variation of conventional comparative genomic hybridization (CGH) has been employed to detect genetic alterations associated with tamoxifen resistance. MCF-7, a tamoxifen-sensitive human breast cancer cells line, and its tamoxifen-resistant clone, CL-9 were used. Both cell lines showed extensive areas of concordance but consistent differences were seen with the acquisition of tamoxifen resistance. These differences included the amplification of 2p16.3 approximately p23.2, 2q21 approximately q34, 3p12.3 approximately p14.1, 3p22 approximately p26, 3q, 12q13.2 approximately q22, 13q12 approximately q14, 17q21.3 approximately q23, 20q11.2 approximately q13.1 and 21q11.2 approximately q21 as well as the deletion of 6p21.1, 6p23 approximately p25, 7q11.1 approximately q31, 7q35 approximately q36, 11p15, 11q24, 13q33, 17p, 18q12 approximately q21.1, 19p, 19q13.3, 22q13.1 approximately q13.2. These findings were supported by conventional cytogenetics and chromosome painting. The regions identified by CGH potentially harbor genes that could be important in the development of tamoxifen resistance.
Achuthan
R
R
Molecular Medicine Unit, University of Leeds, St. James's University Hospital, LS9 7TF, Leeds, UK.
Bell
S M
SM
Roberts
P
P
Leek
J P
JP
Horgan
K
K
Markham
A F
AF
MacLennan
K A
KA
Speirs
V
V
D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002869:Chromosome Aberrations; D020223:Chromosome Painting; D020732:Cytogenetic Analysis; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006801:Humans; D009693:Nucleic Acid Hybridization; D013629:Tamoxifen / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D018931:Antineoplastic Agents, Hormonal; D013629:Tamoxifen