Global characterization of signalling networks associated with tamoxifen resistance in breast cancer

被引：39

作者：

Browne, Brigid C. ^{[1
]}

Hochgrafe, Falko ^{[2
]}

Wu, Jianmin ^{[1
,3
]}

Millar, Ewan K. A. ^{[1
,4
,5
,6
]}

Barraclough, Jane ^{[1
]}

Stone, Andrew ^{[1
]}

McCloy, Rachael A. ^{[1
]}

Lee, Christine S. ^{[1
]}

Roberts, Caroline ^{[1
]}

Ali, Naveid A. ^{[1
]}

Boulghourjian, Alice ^{[1
]}

Schmich, Fabian ^{[7
,8
]}

Linding, Rune ^{[9
]}

Farrow, Lynn ^{[10
]}

Gee, Julia M. W. ^{[10
]}

Nicholson, Robert I. ^{[10
]}

O'Toole, Sandra A. ^{[1
,3
,11
,12
]}

Sutherland, Robert L. ^{[1
,3
]}

Musgrove, Elizabeth A. ^{[1
,3
]}

Butt, Alison J. ^{[1
,3
]}

Daly, Roger J. ^{[1
,3
,13
,14
]}

机构：

[1] Garvan Inst Med Res, Kinghorn Canc Ctr, Canc Res Program, Sydney, NSW, Australia

[2] Ernst Moritz Arndt Univ Greifswald, Jr Res Grp Pathoprote, Competence Ctr Funct Gen, Greifswald, Germany

[3] Univ New S Wales, Fac Med, St Vincents Clin Sch, Darlinghurst, NSW, Australia

[4] Monash Univ, Fac Med, Sch Med Sci, Clayton, Vic 3800, Australia

[5] St George Hosp, S Eastern Area Lab Serv, Dept Anat Pathol, Kogarah, NSW, Australia

[6] Univ Western Sydney, Sch Med & Hlth Sci, Campbelltown, NSW, Australia

[7] Swiss Fed Inst Technol, Dept Biosystems Sci & Engn, Basel, Switzerland

[8] Swiss Inst Bioinformat, Basel, Switzerland

[9] Tech Univ Denmark, Cellular Signal Integrat Grp, Ctr Biol Sequence Anal, Dept Syst Biol, DK-2800 Lyngby, Denmark

[10] Cardiff Univ, Cardiff Sch Pharm & Pharmaceut Sci, Cardiff CF10 3AX, S Glam, Wales

[11] Royal Prince Alfred Hosp, Dept Tissue Pathol & Diagnost Oncol, Camperdown, NSW 2050, Australia

[12] Univ Sydney, Sydney Med Sch, Westmead, NSW 2145, Australia

[13] Monash Univ, Sch Biomed Sci, Dept Biochem & Mol Biol, Clayton, Vic 3800, Australia

[14] Natl Breast Canc Fdn, Res Investment, Sydney, NSW, Australia

来源：

FEBS JOURNAL | 2013年 / 280卷 / 21期

基金：

英国医学研究理事会;

关键词：

endocrine resistance; MARCKS; MCF7; phosphoproteomics; Yes kinase;

D O I：

10.1111/febs.12441

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Acquired resistance to the anti-estrogen tamoxifen remains a significant challenge in breast cancer management. In this study, we used an integrative approach to characterize global protein expression and tyrosine phosphorylation events in tamoxifen-resistant MCF7 breast cancer cells (TamR) compared with parental controls. Quantitative mass spectrometry and computational approaches were combined to identify perturbed signalling networks, and candidate regulatory proteins were functionally interrogated by siRN-Amediated knockdown. Network analysis revealed that cellular metabolism was perturbed in TamR cells, together with pathways enriched for proteins associated with growth factor, cell-cell and cell matrix-initiated signalling. Consistent with known roles for Ras/MAPK and PI3-kinase signalling in tamoxifen resistance, tyrosine-phosphorylated MAPK1, SHC1 and PIK3R2 were elevated in TamR cells. Phosphorylation of the tyrosine kinase Yes and expression of the actin-binding protein myristoylated alanine-rich C-kinase substrate (MARCKS) were increased two-and eightfold in TamR cells respectively, and these proteins were selected for further analysis. Knockdown of either protein in TamR cells had no effect on anti-estrogen sensitivity, but significantly decreased cell motility. MARCKS expression was significantly higher in breast cancer cell lines than normal mammary epithelial cells and in ER-negative versus ER-positive breast cancer cell lines. In primary breast cancers, cytoplasmic MARCKS staining was significantly higher in basal-like and HER2 cancers than in luminal cancers, and was independently predictive of poor survival in multivariate analyses of the whole cohort (P < 0.0001) and in ER-positive patients (P = 0.0005). These findings provide network-level insights into the molecular alterations associated with the tamoxifen-resistant phenotype, and identify MARCKS as a potential biomarker of therapeutic responsiveness that may assist in stratification of patients for optimal therapy.

引用

页码：5237 / 5257

页数：21