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Breast Cancer Research and Treatment

Erschienen in:

07.02.2017 | Preclinical study

Amplification of SOX4 promotes PI3K/Akt signaling in human breast cancer

verfasst von: Gaurav A. Mehta, Joel S. Parker, Grace O. Silva, Katherine A. Hoadley, Charles M. Perou, Michael L. Gatza

Erschienen in: Breast Cancer Research and Treatment | Ausgabe 3/2017

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Abstract

Purpose

The PI3K/Akt signaling axis contributes to the dysregulation of many dominant features in breast cancer including cell proliferation, survival, metabolism, motility, and genomic instability. While multiple studies have demonstrated that basal-like or triple-negative breast tumors have uniformly high PI3K/Akt activity, genomic alterations that mediate dysregulation of this pathway in this subset of highly aggressive breast tumors remain to be determined.

Methods

In this study, we present an integrated genomic analysis based on the use of a PI3K gene expression signature as a framework to analyze orthogonal genomic data from human breast tumors, including RNA expression, DNA copy number alterations, and protein expression. In combination with data from a genome-wide RNA-mediated interference screen in human breast cancer cell lines, we identified essential genetic drivers of PI3K/Akt signaling.

Results

Our in silico analyses identified SOX4 amplification as a novel modulator of PI3K/Akt signaling in breast cancers and in vitro studies confirmed its role in regulating Akt phosphorylation.

Conclusions

Taken together, these data establish a role for SOX4-mediated PI3K/Akt signaling in breast cancer and suggest that SOX4 may represent a novel therapeutic target and/or biomarker for current PI3K family therapies.

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Ciriello G et al (2015) Comprehensive molecular portraits of invasive lobular breast cancer. Cell 163(2):506–519CrossRefPubMedPubMedCentral

Perou CM et al (2000) Molecular portraits of human breast tumors. Nature 406:747–752CrossRefPubMed

Cancer Genome Atlas Network (2012) Comprehensive molecular portraits of human breast tumours. Nature 490(7418):61–70

Curtis C et al (2012) The genomic and transcriptomic architecture of 2000 breast tumours reveals novel subgroups. Nature 486(7403):346–352PubMedPubMedCentral

Sorlie T et al (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 98(19):10869–10874CrossRefPubMedPubMedCentral

Gatza ML et al (2014) An integrated genomics approach identifies drivers of proliferation in luminal-subtype human breast cancer. Nat Genet 46(10):1051–1059CrossRefPubMedPubMedCentral

DeSantis CE et al (2014) Cancer treatment and survivorship statistics, 2014. CA Cancer J Clin 64(4):252–271CrossRefPubMed

Fruman DA, Rommel C (2014) PI3K and cancer: lessons, challenges and opportunities. Nat Rev Drug Discov 13(2):140–156CrossRefPubMedPubMedCentral

Rodon J et al (2013) Development of PI3K inhibitors: lessons learned from early clinical trials. Nat Rev Clin Oncol 10(3):143–153CrossRefPubMed

10.

Wong KK, Engelman JA, Cantley LC (2010) Targeting the PI3K signaling pathway in cancer. Curr Opin Genet Dev 20(1):87–90CrossRefPubMed

11.

Mertins P et al (2016) Proteogenomics connects somatic mutations to signalling in breast cancer. Nature 534(7605):55–62CrossRefPubMedPubMedCentral

12.

Weigman VJ et al (2012) Basal-like Breast cancer DNA copy number losses identify genes involved in genomic instability, response to therapy, and patient survival. Breast Cancer Res Treat 133(3):865–880CrossRefPubMed

13.

Lopez-Knowles E et al (2010) PI3K pathway activation in breast cancer is associated with the basal-like phenotype and cancer-specific mortality. Int J Cancer 126(5):1121–1131CrossRefPubMed

14.

Marty B et al (2008) Frequent PTEN genomic alterations and activated phosphatidylinositol 3-kinase pathway in basal-like breast cancer cells. Breast Cancer Res 10(6):R101CrossRefPubMedPubMedCentral

15.

Hoadley KA et al (2014) Multiplatform analysis of 12 cancer types reveals molecular classification within and across tissues of origin. Cell 158(4):929–944CrossRefPubMedPubMedCentral

16.

Gatza ML et al (2010) A pathway-based classification of human breast cancer. Proc Natl Acad Sci 107:6994–6999CrossRefPubMedPubMedCentral

17.

Hutti JE et al (2012) Oncogenic PI3K mutations lead to NF-kappaB-dependent cytokine expression following growth factor deprivation. Cancer Res 72(13):3260–3269CrossRefPubMedPubMedCentral

18.

Saal LH et al (2007) Poor prognosis in carcinoma is associated with a gene expression signature of aberrant PTEN tumor suppressor pathway activity. Proc Natl Acad Sci USA 104(18):7564–7569CrossRefPubMedPubMedCentral

19.

Parker JS et al (2009) Supervised risk predictor of breast cancer based on intrinsic subtypes. J Clin Oncol 27(8):1160–1167CrossRefPubMedPubMedCentral

20.

Hoeflich KP et al (2009) In vivo antitumor activity of MEK and phosphatidylinositol 3-kinase inhibitors in basal-like breast cancer models. Clin Cancer Res 15(14):4649–4664CrossRefPubMed

21.

Reich M et al (2006) GenePattern 2.0. Nat Genet 38:500–501CrossRefPubMed

22.

Mermel CH et al (2011) GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers. Genome Biol 12(4):R41CrossRefPubMedPubMedCentral

23.

Marcotte R et al (2012) Essential gene profiles in breast, pancreatic, and ovarian cancer cells. Cancer Discov 2(2):172–189CrossRefPubMed

24.

Perou CM et al (2000) Molecular portraits of human breast tumours. Nature 406(6797):747–752CrossRefPubMed

25.

Chapman NM et al (2015) Proline-rich tyrosine kinase 2 controls PI3-kinase activation downstream of the T cell antigen receptor in human T cells. J Leukoc Biol 97(2):285–296CrossRefPubMed

26.

Izumchenko E et al (2009) NEDD9 promotes oncogenic signaling in mammary tumor development. Cancer Res 69(18):7198–7206CrossRefPubMedPubMedCentral

27.

Jafarnejad SM et al (2013) Pleiotropic function of SRY-related HMG box transcription factor 4 in regulation of tumorigenesis. Cell Mol Life Sci 70(15):2677–2696CrossRefPubMed

28.

Vervoort SJ, van Boxtel R, Coffer PJ (2013) The role of SRY-related HMG box transcription factor 4 (SOX4) in tumorigenesis and metastasis: friend or foe? Oncogene 32(29):3397–3409CrossRefPubMed

29.

Miller TW et al (2009) Loss of Phosphatase and Tensin homologue deleted on chromosome 10 engages ErbB3 and insulin-like growth factor-I receptor signaling to promote antiestrogen resistance in breast cancer. Cancer Res 69(10):4192–4201CrossRefPubMedPubMedCentral

30.

Nagata Y et al (2004) PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 6(2):117–127CrossRefPubMed

31.

Perez-Tenorio G, Stal O (2002) Activation of AKT/PKB in breast cancer predicts a worse outcome among endocrine treated patients. Br J Cancer 86(4):540–545CrossRefPubMedPubMedCentral

32.

Stemke-Hale K et al (2008) An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. Cancer Res 68(15):6084–6091CrossRefPubMedPubMedCentral

33.

Bachman KE et al (2004) The PIK3CA gene is mutated with high frequency in human breast cancers. Cancer Biol Ther 3(8):772–775CrossRefPubMed

34.

Campbell IG et al (2004) Mutation of the PIK3CA gene in ovarian and breast cancer. Cancer Res 64(21):7678–7681CrossRefPubMed

35.

Baselga J et al (2012) Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 366(6):520–529CrossRefPubMed

36.

Piccart M et al (2014) Everolimus plus exemestane for hormone-receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: overall survival results from BOLERO-2dagger. Ann Oncol 25(12):2357–2362CrossRefPubMed

37.

Zardavas D, Fumagalli D, Loi S (2012) Phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin pathway inhibition: a breakthrough in the management of luminal (ER+/HER2−) breast cancers? Curr Opin Oncol 24(6):623–634CrossRefPubMed

38.

Zhang J et al (2012) SOX4 induces epithelial-mesenchymal transition and contributes to breast cancer progression. Cancer Res 72(17):4597–4608CrossRefPubMed

39.

Rhodes DR et al (2004) Large-scale meta-analysis of cancer microarray data identifies common transcriptional profiles of neoplastic transformation and progression. Proc Natl Acad Sci USA 101(25):9309–9314CrossRefPubMedPubMedCentral

40.

Liu P et al (2006) Sex-determining region Y box 4 is a transforming oncogene in human prostate cancer cells. Cancer Res 66(8):4011–4019CrossRefPubMed

41.

Tavazoie SF et al (2008) Endogenous human microRNAs that suppress breast cancer metastasis. Nature 451(7175):147–152CrossRefPubMedPubMedCentral

42.

Tiwari N et al (2013) Sox4 is a master regulator of epithelial-mesenchymal transition by controlling Ezh2 expression and epigenetic reprogramming. Cancer Cell 23(6):768–783CrossRefPubMed

43.

Ikushima H et al (2011) Glioma-initiating cells retain their tumorigenicity through integration of the Sox axis and Oct4 protein. J Biol Chem 286(48):41434–41441CrossRefPubMedPubMedCentral

44.

Ramezani-Rad P et al (2013) SOX4 enables oncogenic survival signals in acute lymphoblastic leukemia. Blood 121(1):148–155CrossRefPubMedPubMedCentral

45.

Bilir B et al (2016) SOX4 is essential for prostate tumorigenesis initiated by PTEN ablation. Cancer Res 76(5):1112–1121CrossRefPubMed

46.

Liao YL et al (2008) Identification of SOX4 target genes using phylogenetic footprinting-based prediction from expression microarrays suggests that overexpression of SOX4 potentiates metastasis in hepatocellular carcinoma. Oncogene 27(42):5578–5589CrossRefPubMed

47.

Yeh ES et al (2013) Hunk negatively regulates c-myc to promote Akt-mediated cell survival and mammary tumorigenesis induced by loss of Pten. Proc Natl Acad Sci USA 110(15):6103–6108CrossRefPubMedPubMedCentral

48.

Scharer CD et al (2009) Genome-wide promoter analysis of the SOX4 transcriptional network in prostate cancer cells. Cancer Res 69(2):709–717CrossRefPubMedPubMedCentral

Titel: Amplification of SOX4 promotes PI3K/Akt signaling in human breast cancer
verfasst von: Gaurav A. Mehta
Joel S. Parker
Grace O. Silva
Katherine A. Hoadley
Charles M. Perou
Michael L. Gatza
Publikationsdatum: 07.02.2017
Verlag: Springer US
Erschienen in: Breast Cancer Research and Treatment / Ausgabe 3/2017
Print ISSN: 0167-6806
Elektronische ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-017-4139-2

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Amplification of SOX4 promotes PI3K/Akt signaling in human breast cancer