Profilin-1 Overexpression in MDA-MB-231 Breast Cancer Cells Is Associated with Alterations in Proteomics Biomarkers of Cell Proliferation, Survival, and Motility as Revealed by Global Proteomics Analyses

Abstract

Despite early screening programs and new therapeutic strategies, metastatic breast cancer is still the leading cause of cancer death in women in industrialized countries and regions. There is a need for novel biomarkers of susceptibility, progression, and therapeutic response. Global analyses or systems science approaches with omics technologies offer concrete ways forward in biomarker discovery for breast cancer. Previous studies have shown that expression of profilin-1 (PFN1), a ubiquitously expressed actin-binding protein, is downregulated in invasive and metastatic breast cancer. It has also been reported that PFN1 overexpression can suppress tumorigenic ability and motility/invasiveness of breast cancer cells. To obtain insights into the underlying molecular mechanisms of how elevating PFN1 level induces these phenotypic changes in breast cancer cells, we investigated the alteration in global protein expression profiles of breast cancer cells upon stable overexpression of PFN1 by a combination of three different proteome analysis methods (2-DE, iTRAQ, label-free). Using MDA-MB-231 as a model breast cancer cell line, we provide evidence that PFN1 overexpression is associated with alterations in the expression of proteins that have been functionally linked to cell proliferation (FKPB1A, HDGF, MIF, PRDX1, TXNRD1, LGALS1, STMN1, LASP1, S100A11, S100A6), survival (HSPE1, HSPB1, HSPD1, HSPA5 and PPIA, YWHAZ, CFL1, NME1) and motility (CFL1, CORO1B, PFN2, PLS3, FLNA, FLNB, NME2, ARHGDIB). In view of the pleotropic effects of PFN1 overexpression in breast cancer cells as suggested by these new findings, we propose that PFN1-induced phenotypic changes in cancer cells involve multiple mechanisms. Our data reported here might also offer innovative strategies for identification and validation of novel therapeutic targets and companion diagnostics for persons with, or susceptibility to, breast cancer.

The myocardin-related transcription factor MKL co-regulates the cellular levels of two profilin isoforms

“…Third, Pfn's ability to regulate MKL/SRF (a major transcriptional system) suggests that we should consider additional pathways by which Pfn may regulate actin-dependent processes such as cell migration beyond the traditional model of Pfn's role in regulating actin polymerization at the leading edge as conceived in the literature. In fact, a recent proteomic study by Moens and co-workers and our group revealed that overexpression of Pfn1 in MDA-231 cells is associated with alterations in the expression of many proteins that have been functionally linked to cytoskeletal regulation, adhesion, proliferation, and survival (42). Of particular interest, cofilin1, an SRF target gene (9) and a major regulator of actin cytoskeleton dynamics and cell motility, was shown to be one of the differentially expressed proteins between control and Pfn1overexpressing cells.…”

Profilin-1 mediated cell-cycle arrest: searching for drug targets

“…It has recently been shown that overexpression of Pfn1 in the human breast cancer cell line MDA-MB 231 induces alterations of the expression of a range of proteins involved in cell proliferation, motility and survival. 1 However, the mechanisms underlying the reduced motility and proliferation and increased apoptosis obeserved in these MDA-MB 231 cells are still largely unknown. The study by Jiang et al 2 propose a novel pathway that link Pfn1 overexpression to the phosphorylation of p27 on threonine 198 (T198).…”

A Quantitative Systems Pharmacology Perspective on Cancer Immunology

“…To overcome these barriers to disease modeling, computer simulation using previous molecular interaction and human clinical data may be able to elucidate these signaling network differences [9,87]. Quantitative systems pharmacology is now being used to analyze drug interactions and provide insight to adverse effects, and has been suggested as a method of selecting better drug candidates for development [9].…”