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. 2016 Aug 23;7(34):54488-54502.
doi: 10.18632/oncotarget.10239.

Prognostic significance of PLIN1 expression in human breast cancer

Cefan Zhou  1   2 , Ming Wang  3 , Li Zhou  4 , Yi Zhang  1 , Weiyong Liu  5 , Wenying Qin  1 , Rong He  1 , Yang Lu  1 , Yefu Wang  2 , Xing-Zhen Chen  1   6 , Jingfeng Tang  1
Affiliations

Prognostic significance of PLIN1 expression in human breast cancer

Cefan Zhou et al. Oncotarget. .

Abstract

Breast cancer is a heterogeneous disease associated with diverse clinical, biological and molecular features, presenting huge challenges for prognosis and treatment. Here we found that perilipin-1 (PLIN1) mRNA expression is significantly downregulated in human breast cancer. Kaplan-Meier analysis indicated that patients presenting with reduced PLIN1 expression exhibited poorer overall metastatic relapse-free survival (p = 0.03). Further Cox proportional hazard models analysis revealed that the reduced expression of PLIN1 is an independent predictor of overall survival in estrogen receptor positive (p < 0.0001, HR = 0.87, 95% CI = 0.81-0.92, N = 3,600) and luminal A-subtype (p = 0.02, HR = 0.88, 95% CI = 0.78-0.98, N = 1,469) breast cancer patients. We also demonstrated that the exogenous expression of PLIN1 in human breast cancer MCF-7 and MDA-MB-231 cells significantly inhibits cell proliferation, migration, invasion and in vivo tumorigenesis in mice. Together, these data provide novel insights into a prognostic significance of PLIN1 in human breast cancer and reveal a potentially new gene therapy target for breast cancer.

Keywords: Kaplan-Meier analysis; biomarker; meta analysis; perilipin-1; tumor suppressor.

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Conflict of interest statement

CONFLICTS OF INTEREST

No potential conflicts of interest were disclosed.

Figures

Figure 1
Figure 1. Gene expression patterns in breast cancer tissues
(A–B) A heatmap illustrating genes expression profiles for the 30 breast cancer cases (10 normal and 20 tumors). The log2 values were calculated for each sample by normalizing to read counts alone (log2Fold Change). Heatmap analysis was performed by R version 3.2.2 software with DESeq package (p < 0.05 and log2 Fold Change > 4) (A) and edgeR package (p < 0.05 and log2 Fold Change > 4) (B). Short red and green vertical bars indicate upregulated and downregulated genes, respectively. RNAseq data were downloaded from TCGA database. (C) A Venn diagram of the concordant gene entities by the two algorithms and the top 10 genes, of which 5 were upregulated (red) and 5 were downregulated (green). (D) Analysis for protein-protein interaction by the STRING network identified two major interconnecting clusters with high-degree interactions between the genes (N = 57); three nodes of connection were encircled.
Figure 2
Figure 2. Validation of the PLIN1 gene signature for predicting survival
(A) Kaplan-Meier MR-free overall survival curves using the Bc-GenExMiner v3.2 database (N = 3826). (B) PLIN1 mRNA expression was downregulated in 308 breast cancer samples downloaded from TCGA database. (C) ROC curve of PLIN1 expression in breast cancer patients from normal subjects. The area under the curve (AUC) was 0.93, with a standard error of 0.02 and a 95% confidence interval of 0.89–0.96. (D–E) Forest plots of PLIN1 expression on MR-free (D) and AE-free (E) survival.
Figure 3
Figure 3. Evaluation of PLIN1 as an independent marker for disease outcome in breast cancer patients with different ER statuses and molecular subtypes
(A–B) Kaplan-Meier MR-free survival curves for PLIN1 in ER-positive (A, N = 2,757) and ER-negative (B, N = 1,039) patients. (C–D) Kaplan-Meier AE-free survival curves for PLIN1 in ER-positive (N = 3,600) (A) and ER-negative (N = 1,400) patients. (E–I) Kaplan-Meier AE-free survival curves for PLIN1 within the breast cancer molecular subtypes, including luminal A (E, N = 1,484), HER2-E (F, N = 601), normal breast-like (G, N = 653), luminal B (H, N = 627) and basal-like (I, N = 790) subtypes.
Figure 4
Figure 4. Expression of PLIN1 in breast cancer
Compared with normal tissue (A), immunohistochemical staining revealed a significantly reduced staining area of PLIN1 in HER2-E (B), basal-like (C), luminal A (D) and luminal B (E) subtypes. HER2 staining was used as a control.
Figure 5
Figure 5. Effects of PLIN1 on human breast cancer cell proliferation, migration and invasion
(A) Western blot assay shows the PLIN1 expression levels after transfection with the PLIN1-expressing recombinant plasmids in MCF-7 and MDA-MB-231 cells. (B–C) Cell proliferation analysis by MTT assays for MCF-7 (B) and MDA-MB-231 cells (C) with or without exogenous PLIN1. (D–G) Transwell assays show the effects of PLIN1 on MCF-7 and MDA-MB-231 breast cancer cell migration and invasion. Representative micrographs and statistical data exhibit the effects of PLIN1 on cell migration (D and F) and invasion (E and G). The data are presented as the mean values ± SD. The Two-tailed Student's t-test was used. *p < 0.05, **p < 0.01 and ***p < 0.001. (H) Representative pictures from a total of 6 tested and 6 control mice, showing tumorigenesis of hind limbs isolated from nude mice three weeks after injection of cells stably expressing PLIN1 or control cells.
Figure 6
Figure 6. Correlation of PLIN1 expression with disease outcome in several human cancer types and TP53 somatic mutations
(A–D) Kaplan-Meier survival curves for the patients with low or high levels of PLIN1 in breast cancer (A), low-grade glioma (B), sarcoma (C) and hepatocellular carcinoma (D). (E) Association of PLIN1 expression with somatic TP53, PIK3CA and GATA3 mutations in breast cancer. (F) Association of PLIN1 expression with somatic TP53 mutations in 3 other human cancers. All datasets were obtained from cBioPortal.
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