CtIP silencing as a novel mechanism of tamoxifen resistance in breast cancer.
Acquired resistance to the antiestrogen tamoxifen constitutes a major clinical challenge in breast cancer therapy. However, the mechanisms involved are still poorly understood. Using serial analysis of gene expression, we identified CtIP, a BRCA1- and CtBP-interacting protein, as one of the most significantly down-regulated transcripts in estrogen receptor alpha-positive (ER+) MCF-7 tamoxifen-resistant breast cancer cells. We further confirmed the association of CtIP down-regulation with tamoxifen resistance in an additional ER+ breast cancer line (T47D), strengthening the relevance of the phenomenon observed. In additional studies, we found CtIP protein expression in a majority of ER+ breast cancer cell lines that we tested, but no or very little CtIP expression in ER-negative lines. Furthermore, CtIP protein expression status correlates with clinical response to neoadjuvant endocrine therapy, and patients with progressive disease express significantly lower CtIP protein in their primary breast carcinomas than those who respond. Meta-analysis of seven publicly available gene expression microarray data sets showed that CtIP expression is significantly associated with ER, disease-free survival, and breast cancer metastasis status. Importantly, we found that silencing endogenous CtIP in tamoxifen-sensitive breast cancer cells confers tamoxifen resistance. On the other hand, reexpression of CtIP in tamoxifen-resistant breast cancer cells restores sensitivity to the inhibitory growth effects of tamoxifen. Together, our findings indicate that CtIP silencing might be a novel mechanism for the development of tamoxifen resistance in breast cancer, suggesting that CtIP is likely associated with ER function, and that CtIP gene and protein expression may be useful biomarkers for breast cancer prognosis and clinical management.
Wu
Minhao
M
Department of Carcinogenesis, The University of Texas M. D. Anderson Cancer Center, Science Park Research Division, 1808 Park Road 1C, P.O. Box 389, Smithville, TX 78957, USA.
Soler
David Ramos
DR
Abba
Martin C
MC
Nunez
Maria I
MI
Baer
Richard
R
Hatzis
Christos
C
Llombart-Cussac
Antonio
A
Llombart-Bosch
Antonio
A
Aldaz
C Marcelo
CM
D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000556:secondary; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D018572:Disease-Free Survival; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004706:Endodeoxyribonucleases; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing; D006131:Growth Inhibitors / Q000378:metabolism; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D013629:Tamoxifen / Q000627:therapeutic use*
D018931:Antineoplastic Agents, Hormonal; D002352:Carrier Proteins; D006131:Growth Inhibitors; D009687:Nuclear Proteins; D013629:Tamoxifen; D004706:Endodeoxyribonucleases; C410741:RBBP8 protein, human