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.

Architecture of The Human Ape1 Interactome Defines Novel Cancers Signatures

“…important booster of the transformation process 41 , even though a perfect correlation of gene expression at mRNA and protein levels is not always observed 42 . However, data described in the previous section provided interesting evidences suggesting that the integration of proteomic and transcriptomic data, correlated by common biological functions, may highlight the potential involvement of subsets of genes in neoplastic transformation.…”

Advancement of mass spectrometry-based proteomics technologies to explore triple negative breast cancer

“…A label-free shotgun proteomic approach revealed a signature of 21 proteins in a High Mobility Group A1 (HMG1) silenced TNBC cell line which was associated with poor prognosis 103 . A unique HMG1-linked sub protein signature of three proteins - kinesin family member C1(KIFC1); thyroid hormone receptor interacting protein 13 (TRIP13); and leucine-rich repeat containing 59 (LRRC59) - was unexplored in TNBCs.…”

“…A unique HMG1-linked sub protein signature of three proteins - kinesin family member C1(KIFC1); thyroid hormone receptor interacting protein 13 (TRIP13); and leucine-rich repeat containing 59 (LRRC59) - was unexplored in TNBCs. KIFC1, TRIP13, and LRRC59 proteins are downstream targets of HMG1 and involved in cell motility 103 . Another label-based proteomics study reported that PTPN12, a tyrosine phosphatase, inhibited cellular transformation and metastasis of TNBC cells 104 .…”

Mass spectrometry-assisted gel-based proteomics in cancer biomarker discovery: approaches and application

“…High mobility group protein HMG-I/HMG-Y (HMGA1) abundance level was found to be associated with breast cancer clinicopathological features. Maurizio et al utilized label-free shotgun MS to analyze the proteins extracted from HMGA1-silenced cells and control breast cancer cell line MDA-MB-231 176 . Ning Qing Liu et al evaluated numerous approaches for global proteome quantification and proteins involved in a signaling pathway in breast cancer tissues were identified (Figure 6 c) 177 .…”