PIK3R1 underexpression is an independent prognostic marker in breast cancer

BMC Cancer

Magdalena Cizkova²  Sophie Vacher³  Didier Meseure⁴  Martine Trassard⁴  Aurélie Susini³  Dana Mlcuchova²  Celine Callens³  Etienne Rouleau³  Frederique Spyratos³  Rosette Lidereau³  Ivan Bièche¹ 

[1] Laboratoire d’Oncogénétique, 35 rue Dailly, Institut Curie - Hôpital René Huguenin, St-Cloud F-92210, France

[2] Laboratory of Experimental Medicine, Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University and University Hospital Olomouc, Olomouc, Czech Republic

[3] Oncogenetic Laboratory, Institut Curie, Hospital René Huguenin, Saint-Cloud, France

[4] Department of Pathology, Institut Curie, Hospital René Huguenin, Saint-Cloud, France

关键词: Prognostic value;    Signaling pathways;    Breast cancer subtypes;    Breast cancer;    PIK3CA;    PIK3R1;   

Others  :  859253
DOI  :  10.1186/1471-2407-13-545

 received in 2013-06-11, accepted in 2013-10-28,  发布年份 2013

【 摘 要 】

Background

The present study focused on the prognostic roles of PIK3CA and PIK3R1 genes and additional PI3K pathway-associated genes in breast cancer.

Methods

The mutational and mRNA expression status of PIK3CA, PIK3R1 and AKT1, and expression status of other genes involved in the PI3K pathway (EGFR, PDK1, PTEN, AKT2, AKT3, GOLPH3, WEE1, P70S6K) were assessed in a series of 458 breast cancer samples.

Results

PIK3CA mutations were identified in 151 samples (33.0%) in exons 1, 2, 9 and 20. PIK3R1 mutations were found in 10 samples (2.2%) and underexpression in 283 samples (61.8%). AKT1 mutations were found in 15 samples (3.3%) and overexpression in 116 samples (25.3%). PIK3R1 underexpression tended to mutual exclusivity with PIK3CA mutations (p = 0.00097). PIK3CA mutations were associated with better metastasis-free survival and PIK3R1 underexpression was associated with poorer metastasis-free survival (p = 0.014 and p = 0.00028, respectively). By combining PIK3CA mutation and PIK3R1 expression status, four prognostic groups were identified with significantly different metastasis-free survival (p = 0.00046). On Cox multivariate regression analysis, the prognostic significance of PIK3R1 underexpression was confirmed in the total population (p = 0.0013) and in breast cancer subgroups.

Conclusions

PIK3CA mutations and PIK3R1 underexpression show opposite effects on patient outcome and could become useful prognostic and predictive factors in breast cancer.

【 授权许可】

   
2013 Cizkova et al.; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Katayama K, Fujita N, Tsuruo T: Akt/protein kinase B-dependent phosphorylation and inactivation of WEE1Hu promote cell cycle progression at G2/M transition. Mol Cell Biol 2005, 25:5725-5737.
• [2]Scott KL, Kabbarah O, Liang MC, Ivanova E, Anagnostou V, Wu J, Dhakal S, Wu M, Chen S, Feinberg T, Huang J, Saci A, Widlund HR, Fisher DE, Xiao Y, Rimm DL, Protopopov A, Wong KK, Chin L: GOLPH3 modulates mTOR signalling and rapamycin sensitivity in cancer. Nature 2009, 459:1085-1090.
• [3]Baselga J: Targeting the phosphoinositide-3 (PI3) kinase pathway in breast cancer. Oncologist 2011, 16(Suppl 1):12-19.
• [4]Stemke-Hale K, Gonzalez-Angulo AM, Lluch A, Neve RM, Kuo WL, Davies M, Carey M, Hu Z, Guan Y, Sahin A, Symmans WF, Pusztai L, Nolden LK, Horlings H, Berns K, Hung MC, van de Vijver MJ, Valero V, Gray JW, Bernards R, Mills GB, Hennessy BT: An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. Cancer Res 2008, 68:6084-6091.
• [5]Dunlap J, Le C, Shukla A, Patterson J, Presnell A, Heinrich MC, Corless CL, Troxell ML: Phosphatidylinositol-3-kinase and AKT1 mutations occur early in breast carcinoma. Breast Cancer Res Treat 2010, 120:409-418.
• [6]Castaneda CA, Cortes-Funes H, Gomez HL, Ciruelos EM: The phosphatidyl inositol 3-kinase/AKT signaling pathway in breast cancer. Cancer Metastasis Rev 2010, 29:751-759.
• [7]Shekar SC, Wu H, Fu Z, Yip SC, Nagajyothi Cahill SM, Girvin ME, Backer JM: Mechanism of constitutive phosphoinositide 3-kinase activation by oncogenic mutants of the p85 regulatory subunit. J Biol Chem 2005, 280:27850-27855.
• [8]Barbareschi M, Buttitta F, Felicioni L, Cotrupi S, Barassi F, Del Grammastro M, Ferro A, Dalla Palma P, Galligioni E, Marchetti A: Different prognostic roles of mutations in the helical and kinase domains of the PIK3CA gene in breast carcinomas. Clin Cancer Res 2007, 13:6064-6069.
• [9]Maruyama N, Miyoshi Y, Taguchi T, Tamaki Y, Monden M, Noguchi S: Clinicopathologic analysis of breast cancers with PIK3CA mutations in Japanese women. Clin Cancer Res 2007, 13:408-414.
• [10]Pérez-Tenorio G, Alkhori L, Olsson B, Waltersson MA, Nordenskjöld B, Rutqvist LE, Skoog L, Stål O: PIK3CA mutations and PTEN loss correlate with similar prognostic factors and are not mutually exclusive in breast cancer. Clin Cancer Res 2007, 13:3577-3584.
• [11]Kalinsky K, Jacks LM, Heguy A, Patil S, Drobnjak M, Bhanot UK, Hedvat CV, Traina TA, Solit D, Gerald W, Moynahan ME: PIK3CA mutation associates with improved outcome in breast cancer. Clin Cancer Res 2009, 15:5049-5059.
• [12]Cizkova M, Susini A, Vacher S, Cizeron-Clairac G, Andrieu C, Driouch K, Fourme E, Lidereau R, Bièche I: PIK3CA mutation impact on survival in breast cancer patients and in ERα, PR and ERBB2-based subgroups. Breast Cancer Res 2012, 14:R28. BioMed Central Full Text
• [13]Zhao JJ, Liu Z, Wang L, Shin E, Loda MF, Roberts TM: The oncogenic properties of mutant p110alpha and p110beta phosphatidylinositol 3-kinases in human mammary epithelial cells. Proc Natl Acad Sci U S A 2005, 102:18443-18448.
• [14]Bader AG, Kang S, Vogt PK: Cancer-specific mutations in PIK3CA are oncogenic in vivo. Proc Natl Acad Sci U S A 2006, 103:1475-1479.
• [15]Cheung LW, Hennessy BT, Li J, Yu S, Myers AP, Djordjevic B, Lu Y, Stemke-Hale K, Dyer MD, Zhang F, Ju Z, Cantley LC, Scherer SE, Liang H, Lu KH, Broaddus RR, Mills G: High frequency of PIK3R1 and PIK3R2 mutations in endometrial cancer elucidates a novel mechanism for regulation of PTEN protein stability. Cancer Discov 2011, 1:170-185.
• [16]Taniguchi CM, Winnay J, Kondo T, Bronson RT, Guimaraes AR, Alemán JO, Luo J, Stephanopoulos G, Weissleder R, Cantley LC, Kahn CR: The phosphoinositide 3-kinase regulatory subunit p85alpha can exert tumor suppressor properties through negative regulation of growth factor signaling. Cancer Res 2010, 70:5305-5315.
• [17]Network CGA: Comprehensive molecular portraits of human breast tumours. Nature 2012, 49:61-70.
• [18]Saal LH, Holm K, Maurer M, Memeo L, Su T, Wang X, Yu JS, Malmström PO, Mansukhani M, Enoksson J, Hibshoosh H, Borg A, Parsons R: PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Res 2005, 65:2554-2559.
• [19]Li SY, Rong M, Grieu F, Iacopetta B: PIK3CA mutations in breast cancer are associated with poor outcome. Breast Cancer Res Treat 2006, 96:91-95.
• [20]Bièche I, Onody P, Laurendeau I, Olivi M, Vidaud D, Lidereau R, Vidaud M: Real-time reverse transcription-PCR assay for future management of ERBB2-based clinical applications. Clin Chem 1999, 45:1148-1156.
• [21]Bièche I, Parfait B, Laurendeau I, Girault I, Vidaud M, Lidereau : Quantification of estrogen receptor alpha and beta expression in sporadic breast cancer. Oncogene 2001, 20:8109-8115.
• [22]Onody P, Bertrand F, Muzeau F, Bièche I, Lidereau R: Fluorescence in situ hybridization and immunohistochemical assays for HER-2/neu status determination: application to node-negative breast cancer. Arch Pathol Lab Med 2001, 125:746-750.
• [23]Bossard C, Bieche I, Le Doussal V, Lidereau R, Sabourin JC: Real-time RT-PCR: a complementary method to detect HER-2 status in breast carcinoma. Anticancer Res 2005, 25:4679-4683.
• [24]Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958, 53:457-481.
• [25]Peto R, Pike MC, Armitage P: Design and analysis of randomized clinical trials requiring prolonged observation of each patient: II: analysis and examples. Br J Cancer 1977, 35:1-39.
• [26]Cox DR: Regression models and life-tables. J R Stat Soc Series B Stat Methodol 1972, 34:187-220.
• [27]Meseure D, Vacher S, Drak Alsibai K, Trassard M, Susini A, Le Ray C, Lerebours F, Le Scodan R, Spyratos F, Marc Guinebretiere J, Lidereau R, Bieche I: Profiling of EGFR mRNA and protein expression in 471 breast cancers compared with 10 normal tissues: a candidate biomarker to predict EGFR inhibitor effectiveness. Int J Cancer 2012, 131:1009-1010.
• [28]Jaiswal BS, Janakiraman V, Kljavin NM, Chaudhuri S, Stern HM, Wang W, Kan Z, Dbouk HA, Peters BA, Waring P, Dela Vega T, Kenski DM, Bowman KK, Lorenzo M, Li H, Wu J, Modrusan Z, Stinson J, Eby M, Yue P, Kaminker JS, de Sauvage FJ, Backer JM, Seshagiri S: Somatic mutations in p85alpha promote tumorigenesis through class IA PI3K activation. Cancer Cell 2009, 16:463-474.
• [29]Ellis MJ, Ding L, Shen D, Luo J, Suman VJ, Wallis JW, Van Tine BA, Hoog J, Goiffon RJ, Goldstein TC, Ng S, Lin L, Crowder R, Snider J, Ballman K, Weber J, Chen K, Koboldt DC, Kandoth C, Schierding WS, McMichael JF, Miller CA, Lu C, Harris CC, McLellan MD, Wendl MC, DeSchryver K, Allred DC, Esserman L, Unzeitig G, Margenthaler J, Babiera GV, Marcom PK, Guenther JM, Leitch M, Hunt K, Olson J, Tao Y, Maher CA, Fulton LL, Fulton RS, Harrison M, Oberkfell B, Du F, Demeter R, Vickery TL, Elhammali A, Piwnica-Worms H, McDonald S, Watson M, Dooling DJ, Ota D, Chang LW, Bose R, Ley TJ, Piwnica-Worms D, Stuart JM, Wilson RK, Mardis ER: Whole-genome analysis informs breast cancer response to aromatase inhibition. Nature 2012, 486:353-360.
• [30]Yu J, Zhang Y, McIlroy J, Rordorf-Nikolic T, Orr GA, Backer JM: Regulation of the p85/p110 phosphatidylinositol 3’-kinase: stabilization and inhibition of the p110alpha catalytic subunit by the p85 regulatory subunit. Mol Cell Biol 1998, 18:1379-1387.
• [31]Di Cosimo S, Baselga J: Phosphoinositide 3-kinase mutations in breast cancer: a “good” activating mutation? Clin Cancer Res 2009, 15:5017-5019.
• [32]Dave B, Migliaccio I, Gutierrez MC, Wu MF, Chamness GC, Wong H, Narasanna A, Chakrabarty A, Hilsenbeck SG, Huang J, Rimawi M, Schiff R, Arteaga C, Osborne CK, Chang JC: Loss of phosphatase and tensin homolog or phosphoinositol-3 kinase activation and response to trastuzumab or lapatinib in human epidermal growth factor receptor 2-overexpressing locally advanced breast cancers. J Clin Oncol 2011, 29:166-173.
• [33]Jensen JD, Knoop A, Laenkholm AV, Grauslund M, Jensen MB, Santoni-Rugiu E, Andersson M, Ewertz M: PIK3CA mutations, PTEN, and pHER2 expression and impact on outcome in HER2-positive early-stage breast cancer patients treated with adjuvant chemotherapy and trastuzumab. Ann Oncol 2012, 23:2034-2042.
• [34]Uchino M, Kojima H, Wada K, Imada M, Onoda F, Satofuka H, Utsugi T, Murakami Y: Nuclear beta-catenin and CD44 upregulation characterize invasive cell populations in non-aggressive MCF-7 breast cancer cells. BMC Cancer 2010, 10:414. BioMed Central Full Text
• [35]Lu Y, Lemon W, Liu PY, Yi Y, Morrison C, Yang P, Sun Z, Szoke J, Gerald WL, Watson M, Govindan R, You M: A gene expression signature predicts survival of patients with stage I non-small cell lung cancer. PLoS Med 2006, 3:e467.
• [36]Serão NV, Delfino KR, Southey BR, Beever JE, Rodriguez-Zas SL: Cell cycle and aging, morphogenesis, and response to stimuli genes are individualized biomarkers of glioblastoma progression and survival. BMC Med Genomics 2011, 4:49. BioMed Central Full Text
• [37]Weber GL, Parat MO, Binder ZA, Gallia GL, Riggins GJ: Abrogation of PIK3CA or PIK3R1 reduces proliferation, migration, and invasion in glioblastoma multiforme cells. Oncotarget 2011, 2:833-849.
• [38]Tanaka H, Yoshida M, Tanimura H, Fujii T, Sakata K, Tachibana Y, Ohwada J, Ebiike H, Kuramoto S, Morita K, Yoshimura Y, Yamazaki T, Ishii N, Kondoh O, Aoki Y: The selective class I PI3K inhibitor CH5132799 targets human cancers harboring oncogenic PIK3CA mutations. Clin Cancer Res 2011, 17:3272-3281.
• [39]Kataoka Y, Mukohara T, Shimada H, Saijo N, Hirai M, Minami H: Association between gain-of-function mutations in PIK3CA and resistance to HER2-targeted agents in HER2-amplified breast cancer cell lines. Ann Oncol 2010, 21:255-262.