title: Translating Proteomic Into Functional Data: An High Mobility Group A1 (HMGA1) Proteomic Signature Has Prognostic Value in Breast Cancer.
abstract: Cancer is a very heterogeneous disease, and biological variability adds a further level of complexity, thus limiting the ability to identify new genes involved in cancer development. Oncogenes whose expression levels control cell aggressiveness are very useful for developing cellular models that permit differential expression screenings in isogenic contexts. HMGA1 protein has this unique property because it is a master regulator in breast cancer cells that control the transition from a nontumorigenic epithelial-like phenotype toward a highly aggressive mesenchymal-like one. The proteins extracted from HMGA1-silenced and control MDA-MB-231 cells were analyzed using label-free shotgun mass spectrometry. The differentially expressed proteins were cross-referenced with DNA microarray data obtained using the same cellular model and the overlapping genes were filtered for factors linked to poor prognosis in breast cancer gene expression meta-data sets, resulting in an HMGA1 protein signature composed of 21 members (HRS, HMGA1 reduced signature). This signature had a prognostic value (overall survival, relapse-free survival, and distant metastasis-free survival) in breast cancer. qRT-PCR, Western blot, and immunohistochemistry analyses validated the link of three members of this signature (KIFC1, LRRC59, and TRIP13) with HMGA1 expression levels both in vitro and in vivo and wound healing assays demonstrated that these three proteins are involved in modulating tumor cell motility. Combining proteomic and genomic data with the aid of bioinformatic tools, our results highlight the potential involvement in neoplastic transformation of a restricted list of factors with an as-yet-unexplored role in cancer. These factors are druggable targets that could be exploited for the development of new, targeted therapeutic approaches in triple-negative breast cancer.
authors.affiliation: From the ‡Department of Life Sciences, University of Trieste, 34127 Trieste, Italy;
authors.forename: Elisa
authors.initials: E
authors.lastname: Maurizio
authors.affiliation: §Biochemical Proteomics Group, Department of Proteomics and Signal Transduction, Max-Planck-Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany;
authors.forename: Jacek R
authors.initials: JR
authors.lastname: Wiśniewski
authors.affiliation: ¶Laboratorio Nazionale CIB, (LNCIB), Area Science Park, 34149 Trieste, Italy;
authors.forename: Yari
authors.initials: Y
authors.lastname: Ciani
authors.affiliation: ¶¶Laboratory of Experimental Oncology and Pharmacogenomics IRCCS - Salvatore Maugeri Foundation, 27100 Pavia, Italy;
authors.forename: Angela
authors.initials: A
authors.lastname: Amato
authors.affiliation: From the ‡Department of Life Sciences, University of Trieste, 34127 Trieste, Italy;
authors.forename: Laura
authors.initials: L
authors.lastname: Arnoldo
authors.affiliation: From the ‡Department of Life Sciences, University of Trieste, 34127 Trieste, Italy;
authors.forename: Carlotta
authors.initials: C
authors.lastname: Penzo
authors.affiliation: From the ‡Department of Life Sciences, University of Trieste, 34127 Trieste, Italy;
authors.forename: Silvia
authors.initials: S
authors.lastname: Pegoraro
authors.affiliation: From the ‡Department of Life Sciences, University of Trieste, 34127 Trieste, Italy;
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Giancotti
authors.affiliation: ‖Department of Medical Oncology, Hospital Papa Giovanni XXIII, 24127 Bergamo, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Zambelli
authors.affiliation: ¶Laboratorio Nazionale CIB, (LNCIB), Area Science Park, 34149 Trieste, Italy;
authors.forename: Silvano
authors.initials: S
authors.lastname: Piazza
authors.affiliation: From the ‡Department of Life Sciences, University of Trieste, 34127 Trieste, Italy; rsgarra@units.it manfiole@units.it.
authors.forename: Guidalberto
authors.initials: G
authors.lastname: Manfioletti
authors.affiliation: From the ‡Department of Life Sciences, University of Trieste, 34127 Trieste, Italy; rsgarra@units.it manfiole@units.it.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Sgarra
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D018572:Disease-Free Survival; D015972:Gene Expression Regulation, Neoplastic; D025741:HMGA1a Protein / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D016547:Kinesins / Q000235:genetics / Q000378:metabolism; D013058:Mass Spectrometry; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D015999:Multivariate Analysis; D011379:Prognosis; D020543:Proteome / Q000235:genetics / Q000378:metabolism*; D040901:Proteomics / Q000379:methods*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D057170:Translational Research, Biomedical / Q000379:methods
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C486566:KIFC1 protein, human; C574205:LRRC59 protein, human; D008565:Membrane Proteins; D020543:Proteome; D025741:HMGA1a Protein; D000074183:ATPases Associated with Diverse Cellular Activities; C575259:TRIP13 protein, human; D016547:Kinesins