Identification of TACC1, NOV, and PTTG1 as new candidate genes associated with endocrine therapy resistance in breast cancer.
Cross-resistance to molecules used in endocrine therapy is among the main challenges in the treatment of estrogen receptor-alpha (ERalpha) positive breast cancer. In this study, we used two different cell models of resistance to anti-estrogens: MVLN/CL6.7 cells and VP229/VP267 cells selected after exposure to tamoxifen respectively in vitro and in vivo to characterize a phenotype rarely observed, i.e. acquisition of cross-resistance to the pure ER antagonist fulvestrant. As MVLN/CL6.7 cells and VP229/VP267 cell lines are original and valuable models of cross-resistance to tamoxifen and fulvestrant, we examined candidate genes using a RTQ-PCR strategy to identify new biomarkers of endocrine resistance. Out of the 26 candidate genes tested, 19 displayed deregulation of expression at the basal level in at least one of the two resistant cell lines. Eight genes (TACC1, NOV, PTTG1, MAD2L1, BAK1, TGFB2, BIRC5, and CCNE2) were significantly overexpressed in samples from ER-positive breast cancer patients who relapsed after tamoxifen treatment (n=24) compared with samples from patients who did not (n=24). Five genes (TACC1, NOV, PTTG1, BAK1, and TGFB2) were correlated with significantly shorter relapse-free survival (univariate analysis). Finally, we identified TACC1 and a three-gene expression signature (TACC1, NOV, and PTTG1) as independent prognostic markers (multivariate analysis). Aberrant mRNA and protein levels of TACC1, NOV, and PTTG1 were also observed under tamoxifen and/or fulvestrant exposure in resistant CL6.7 cells compared with their respective control MVLN cells. In conclusion, our data identify TACC1, NOV, and PTTG1 as promising new markers that could be used in the clinical management of ER-positive breast cancer patients.
Ghayad
Sandra E
SE
Université de Lyon, 69008 Lyon, France Université Lyon 1, ISPB, Faculté de Pharmacie de Lyon, 69008 Lyon, France INSERM, U590, 69008 Lyon, France.
Vendrell
Julie A
JA
Bieche
Ivan
I
Spyratos
Frédérique
F
Dumontet
Charles
C
Treilleux
Isabelle
I
Lidereau
Rosette
R
Cohen
Pascale A
PA
D000368:Aged; D000369:Aged, 80 and over; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics; D001943:Breast Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D005326:Fetal Proteins / Q000235:genetics* / Q000378:metabolism; D000077267:Fulvestrant; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D052138:Genes, Neoplasm; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D055514:Nephroblastoma Overexpressed Protein / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012008:Recurrence; D064249:Securin; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use
D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; C526319:CCN3 protein, human; D005326:Fetal Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D055514:Nephroblastoma Overexpressed Protein; D009687:Nuclear Proteins; D012333:RNA, Messenger; D064249:Securin; C120584:TACC1 protein, human; C578002:pituitary tumor-transforming protein 1, human; D013629:Tamoxifen; C016601:afimoxifene; D000077267:Fulvestrant; D004958:Estradiol