دورية أكاديمية
أعرض في EDS

Patient-derived xenografts of triple-negative breast cancer reproduce molecular features of patient tumors and respond to mTOR inhibition.

التفاصيل البيبلوغرافية
العنوان: Patient-derived xenografts of triple-negative breast cancer reproduce molecular features of patient tumors and respond to mTOR inhibition.
المؤلفون: Zhang H, Cohen AL, Krishnakumar S, Wapnir IL, Veeriah S, Deng G, Coram MA, Piskun CM, Longacre TA, Herrler M, Frimannsson DO, Telli ML, Dirbas FM, Matin AC, Dairkee SH, Larijani B, Glinsky GV, Bild AH, Jeffrey SS
المصدر: Breast cancer research : BCR [Breast Cancer Res] 2014 Apr 07; Vol. 16 (2), pp. R36. Date of Electronic Publication: 2014 Apr 07.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: BioMed Central Ltd Country of Publication: England NLM ID: 100927353 Publication Model: Electronic Cited Medium: Internet ISSN: 1465-542X (Electronic) Linking ISSN: 14655411 NLM ISO Abbreviation: Breast Cancer Res Subsets: MEDLINE
أسماء مطبوعة: Publication: London, UK : BioMed Central Ltd
Original Publication: London, UK : Current Science, c1999-
مواضيع طبية MeSH: Antineoplastic Agents/*therapeutic use , TOR Serine-Threonine Kinases/*antagonists & inhibitors , Triple Negative Breast Neoplasms/*drug therapy , Xenograft Model Antitumor Assays/*methods, Animals ; Blotting, Western ; Cell Line, Tumor ; Class I Phosphatidylinositol 3-Kinases ; Comparative Genomic Hybridization ; DNA Mutational Analysis ; Doxorubicin/therapeutic use ; Female ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Immunohistochemistry ; MCF-7 Cells ; Mice ; Mutation ; Oligonucleotide Array Sequence Analysis ; Phosphatidylinositol 3-Kinases/genetics ; Phosphorylation/drug effects ; Ribosomal Protein S6 Kinases, 70-kDa/genetics ; Ribosomal Protein S6 Kinases, 70-kDa/metabolism ; Sirolimus/analogs & derivatives ; Sirolimus/therapeutic use ; TOR Serine-Threonine Kinases/genetics ; TOR Serine-Threonine Kinases/metabolism ; Transcriptome/drug effects ; Triple Negative Breast Neoplasms/genetics ; Triple Negative Breast Neoplasms/metabolism
مستخلص: Introduction: Triple-negative breast cancer (TNBC) is aggressive and lacks targeted therapies. Phosphatidylinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathways are frequently activated in TNBC patient tumors at the genome, gene expression and protein levels, and mTOR inhibitors have been shown to inhibit growth in TNBC cell lines. We describe a panel of patient-derived xenografts representing multiple TNBC subtypes and use them to test preclinical drug efficacy of two mTOR inhibitors, sirolimus (rapamycin) and temsirolimus (CCI-779).
Methods: We generated a panel of seven patient-derived orthotopic xenografts from six primary TNBC tumors and one metastasis. Patient tumors and corresponding xenografts were compared by histology, immunohistochemistry, array comparative genomic hybridization (aCGH) and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) sequencing; TNBC subtypes were determined. Using a previously published logistic regression approach, we generated a rapamycin response signature from Connectivity Map gene expression data and used it to predict rapamycin sensitivity in 1,401 human breast cancers of different intrinsic subtypes, prompting in vivo testing of mTOR inhibitors and doxorubicin in our TNBC xenografts.
Results: Patient-derived xenografts recapitulated histology, biomarker expression and global genomic features of patient tumors. Two primary tumors had PIK3CA coding mutations, and five of six primary tumors showed flanking intron single nucleotide polymorphisms (SNPs) with conservation of sequence variations between primary tumors and xenografts, even on subsequent xenograft passages. Gene expression profiling showed that our models represent at least four of six TNBC subtypes. The rapamycin response signature predicted sensitivity for 94% of basal-like breast cancers in a large dataset. Drug testing of mTOR inhibitors in our xenografts showed 77 to 99% growth inhibition, significantly more than doxorubicin; protein phosphorylation studies indicated constitutive activation of the mTOR pathway that decreased with treatment. However, no tumor was completely eradicated.
Conclusions: A panel of patient-derived xenograft models covering a spectrum of TNBC subtypes was generated that histologically and genomically matched original patient tumors. Consistent with in silico predictions, mTOR inhibitor testing in our TNBC xenografts showed significant tumor growth inhibition in all, suggesting that mTOR inhibitors can be effective in TNBC, but will require use with additional therapies, warranting investigation of optimal drug combinations.
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معلومات مُعتمدة: R01 GM085601 United States GM NIGMS NIH HHS; R01GM085601 United States GM NIGMS NIH HHS; UH3 TR000902 United States TR NCATS NIH HHS; UH2 TR000902 United States TR NCATS NIH HHS; United Kingdom CRUK_ Cancer Research UK
المشرفين على المادة: 0 (Antineoplastic Agents)
624KN6GM2T (temsirolimus)
80168379AG (Doxorubicin)
EC 2.7.1.1 (MTOR protein, human)
EC 2.7.1.137 (Class I Phosphatidylinositol 3-Kinases)
EC 2.7.1.137 (PIK3CA protein, human)
EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa)
EC 2.7.11.1 (TOR Serine-Threonine Kinases)
EC 2.7.11.1 (ribosomal protein S6 kinase, 70kD, polypeptide 1)
W36ZG6FT64 (Sirolimus)
تواريخ الأحداث: Date Created: 20140409 Date Completed: 20150206 Latest Revision: 20211203
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC4053092
DOI: 10.1186/bcr3640
PMID: 24708766
قاعدة البيانات: MEDLINE
الوصف
تدمد:1465-542X
DOI:10.1186/bcr3640