Association of FABP5 Expression With Poor Survival in Triple-Negative Breast Cancer

Abstract

Recent studies using animal models suggest that expression of FABP5 drives the stimulation of cell growth observed in estrogen receptor (ER)-negative breast cancer cells on exposure to retinoic acid (RA). The purpose of this study was to investigate the clinicopathological significance of FABP5 in breast cancer and to evaluate FABP5 as a prognostic marker and a possible novel therapeutic target in breast cancer. Gene expression microarray analysis revealed a significant correlation between elevated FABP5 RNA levels and ER/ progesterone receptor (PR)-negative status, high tumor grade, and poor prognosis. Tissue microarray analysis demonstrated similar correlations with cytoplasmic FABP5 protein. Based on multivariate proportional regression analysis, cytoplasmic FABP5 is a significant and independent prognostic marker of overall survival and recurrence-free survival in breast cancer. The effects of FABP5 on tumor growth appear to be mediated primarily through cytoplasmic FABP, because no correlation was found between nuclear FABP5 and ER/PRnegative status, recurrence, and survival. FABP5 knockdown in breast cancer cell lines demonstrates a correlation between FABP5 levels and growth response to RA. We propose a model whereby growth-promoting FABP5 competes with growth-inhibiting CRABP2 for RA, with retention of RA in the cytoplasm by FABP5 preventing the inhibition of tumor growth. (Am J Pathol

Molecular features of triple negative breast cancer cells by genome-wide gene expression profiling analysis

“…Table Ⅱ lists the 301 upregulated genes in TNBC, including ubiquitin-conjugating enzyme E2C (UBE2C) (14), S100 calcium binding protein P (S100P) (15), ubiquitin carboxyl-terminal esterase L1 (ubiquitin thiolesterase) (UCHL1) (16), pituitary tumor-transforming 1 (PTTG1) (17), ubiquitinconjugating enzyme E2T (UBE2T) (13), ubiquitin-like with PHD and ring finger domains 1 (UHRF1) (18), SIX homeobox 1 (SIX1) (19), and protein regulator of cytokinesis 1 (PRC1) (20), which were previously reported to be overexpressed in breast cancer and involved in mammary carcinogenesis. In particular, topoisomerase (DNA) Ⅱα (TOP2A) (21,22), HORMA domain containing 1 (HORMAD1) (23), ATPase family, Fatty acid binding protein 5 (psoriasis-associated) (FABP5) (24), and AAA domain containing 2 (ATAD2) (25) were previously reported to be potentially involved in the carcinogenesis of TNBC, and to serve as prognostic markers or therapeutic targets for TNBC.…”

Tumor suppressor gene <italic>NGX6</italic> induces changes in protein expression profiles in colon cancer HT-29 cells

“…GNB2 is closely related to tumor metastasis and invasion [7]. FABP5 is involved in the proliferation, metastasis, and apoptosis of various cancer cells [8][9][10]. To validate the results of MALDI-TOF-MS/MS, the expression of these four proteins was detected by western blot in pcDNA3.1(þ)/HT-29 and pcDNA3.1(þ)/NGX6/HT-29 cells.…”

“…FABP5 is associated with the development and metastasis of a variety of tumors [8][9][10], and is a peroxisome proliferator-activated receptor (PPAR-g) ligand [25]. The activation of PPAR-g can induce increases in protein phosphatase 2 (PP2), and then negatively regulate MAPK, ERK, and other signaling pathways in controlling the proliferation and metastasis of tumor cells.…”

FABP5 (fatty acid binding protein 5 (psoriasis-associated))

“…FABP5 can also be upregulated by EGFR signaling in breast cancer cells and serves as a critical mediator of EGFR-induced cell proliferation (Kannan-Thulasiraman et al, 2010). Analysis of a cohort of 120 breast cancer patients revealed an association between elevated levels of cytoplasmic FABP5, high tumor grade, reduced recurrence-free survival and poor prognosis in triple-negative breast cancer (Liu et al, 2011) (see Figure). Recently, genetic ablation of FABP5 was shown to suppress Her-2-induced mammary tumorigenesis, indicating a potential role for FABP5 as a chemotherapeutic target (Levi et al, 2013).…”

“…Recently, genetic ablation of FABP5 was shown to suppress Her-2-induced mammary tumorigenesis, indicating a potential role for FABP5 as a chemotherapeutic target (Levi et al, 2013). Manipulation of FABP5 levels in human breast cancer cell lines and cell lines generated from breast cancer mouse models demonstrates a correlation between FABP5 levels and response to RA treatment (Schug et al, 2007;Schug et al, 2008;Liu et al, 2011). It has been hypothesized that FABP5 confers resistance to RA therapy through competition with CRABP2 for RA, with FABP5 promoting proliferation and survival through activation of PPARβ and CRABP2 inhibiting proliferation through activation of the nuclear retinoic acid receptor (RAR) (Schug et al, 2007;Schug et al, 2008;Liu et al, 2011).…”