title: Tumor Evolution Inferred by Patterns of microRNA Expression through the Course of Disease, Therapy, and Recurrence in Breast Cancer.
abstract: Molecular evolution of tumors during progression, therapy, and metastasis is a major clinical challenge and the main reason for resistance to therapy. We hypothesized that microRNAs (miRNAs) that exhibit similar variation of expression through the course of disease in several patients have a significant function in the tumorigenic process.
  
  
  
  Exploration of evolving disease by profiling 800 miRNA expression from serial samples of individual breast cancer patients at several time points: pretreatment, posttreatment, lymph nodes, and recurrence sites when available (58 unique samples from 19 patients). Using a dynamic approach for analysis, we identified expression modulation patterns and classified varying miRNAs into one of the eight possible temporal expression patterns.
  
  
  
  The various patterns were found to be associated with different tumorigenic pathways. The dominant pattern identified an miRNA set that significantly differentiated between disease stages, and its pattern in each patient was also associated with response to therapy. These miRNAs were related to tumor proliferation and to the cell-cycle pathway, and their mRNA targets showed anticorrelated expression. Interestingly, the level of these miRNAs was lowest in matched recurrent samples from distant metastasis, indicating a gradual increase in proliferative potential through the course of disease. Finally, the average expression level of these miRNAs in the pretreatment biopsy was significantly different comparing patients experiencing recurrence to recurrence-free patients.
  
  
  
  Serial tumor sampling combined with analysis of temporal expression patterns enabled to pinpoint significant signatures characterizing breast cancer progression, associated with response to therapy and with risk of recurrence. Clin Cancer Res; 22(14); 3651-62. ©2016 AACR.
authors.affiliation: Cancer Research Center, Sheba Medical Center, Tel-Hashomer, Israel. Maya.dadiani@sheba.health.gov.il.
authors.forename: Maya
authors.initials: M
authors.lastname: Dadiani
authors.affiliation: Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Noa
authors.initials: N
authors.lastname: Bossel Ben-Moshe
authors.affiliation: Oncology Institute, Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Shani
authors.initials: S
authors.lastname: Paluch-Shimon
authors.affiliation: Cancer Research Center, Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Gili
authors.initials: G
authors.lastname: Perry
authors.affiliation: Pathology Institute, Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Nora
authors.initials: N
authors.lastname: Balint
authors.affiliation: Pathology Institute, Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Irina
authors.initials: I
authors.lastname: Marin
authors.affiliation: Pathology Institute, Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Anya
authors.initials: A
authors.lastname: Pavlovski
authors.affiliation: Cancer Research Center, Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Dana
authors.initials: D
authors.lastname: Morzaev
authors.affiliation: Cancer Research Center, Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Smadar
authors.initials: S
authors.lastname: Kahana-Edwin
authors.affiliation: Pathology Institute, Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Ady
authors.initials: A
authors.lastname: Yosepovich
authors.affiliation: Oncology Institute, Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Einav Nili
authors.initials: EN
authors.lastname: Gal-Yam
authors.affiliation: Oncology Institute, Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Raanan
authors.initials: R
authors.lastname: Berger
authors.affiliation: Pathology Institute, Sheba Medical Center, Tel-Hashomer, Israel. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Iris
authors.initials: I
authors.lastname: Barshack
authors.affiliation: Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Eytan
authors.initials: E
authors.lastname: Domany
authors.affiliation: Oncology Institute, Sheba Medical Center, Tel-Hashomer, Israel. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Bella
authors.initials: B
authors.lastname: Kaufman
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D063646:Carcinogenesis / Q000473:pathology; D002453:Cell Cycle / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D008198:Lymph Nodes / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000473:pathology*; D011446:Prospective Studies; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D035683:MicroRNAs; D012333:RNA, Messenger