Analysis of <i>PLIN</i> gene family as prognostic biomarkers associated with immune infiltration in breast cancer_West China Medical Journal

Authors：

WANG Jialuo ,  ZHANG Yingying

Department of Radiation Oncology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P. R. China;

Corresponding?author：

ZHANG Yingying, Email: csuzhangyingying@163.com

Keywords：

Breast cancer; perilipin; bioinformatics analysis; prognosis; immune infiltration

DOI：

10.7507/1002-0179.202503015

Video：

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Objective To investigate the expression patterns of the perilipin (PLIN) gene family in breast cancer and their associations with immune infiltration and prognosis, thereby identifying potential diagnostic, prognostic, and immunotherapeutic targets for breast cancer. Methods RNA-sequencing data and corresponding clinical information for breast cancer patients were obtained from The Cancer Genome Atlas and the Genotype-Tissue Expression databases. Differential expression of PLIN1-PLIN5 was analyzed using the Wilcoxon test. Receiver operator characteristic curves were generated to evaluate diagnostic performance, and protein expression levels were validated using the Human Protein Atlas database. Associations between gene expression and clinicopathological characteristics were assessed using UALCAN and Bc-GenExMiner v4.5. Prognostic value was evaluated using the Kaplan-Meier Plotter database. The CIBERSORT algorithm was applied to quantify the relative abundance of 22 immune cell types. Pearson correlation analysis was performed to explore the relationship between PLIN1-PLIN5 expression and immune infiltration, followed by functional enrichment analysis. Results Compared with normal breast tissues, PLIN1, PLIN2, PLIN4, and PLIN5 were significantly downregulated in breast cancer tissues, whereas PLIN3 was upregulated. Low expression of PLIN1, PLIN4, and PLIN5 was significantly associated with shorter overall survival and relapse-free survival. Immune infiltration analysis revealed that members of the PLIN family were significantly correlated with multiple immune cell subsets within the tumor immune microenvironment. Specifically, PLIN1 and PLIN5 expression showed positive correlations with activated CD4⁺ T cells, M1 macrophages, and activated myeloid dendritic cells. PLIN3 expression was positively correlated with M1 macrophages, activated natural killer cells, and CD8⁺ T cells, but negatively correlated with M2 macrophages. Functional enrichment analysis indicated that PLIN-related genes were enriched in epithelial-mesenchymal transition, inflammatory response, and transforming growth factor-β signaling pathways, suggesting that the PLIN family may participate in immune evasion processes in breast cancer by regulating immune cell recruitment. Conclusions Comprehensive bioinformatics analysis indicates that PLIN1, PLIN4, and PLIN5 may serve as promising prognostic biomarkers for breast cancer and are closely linked to immune infiltration in breast cancer, suggesting their potential as therapeutic targets.

Citation： WANG Jialuo, ZHANG Yingying. Analysis of PLIN gene family as prognostic biomarkers associated with immune infiltration in breast cancer. West China Medical Journal, 2026, 41(3): 460-467. doi: 10.7507/1002-0179.202503015 Copy

1.	Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2024, 74(3): 229-263.
2.	Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin, 2024, 74(1): 12-49.
3.	Wang Z, Yang L, Wu P, et al. The circROBO1/KLF5/FUS feedback loop regulates the liver metastasis of breast cancer by inhibiting the selective autophagy of afadin. Mol Cancer, 2022, 21(1): 29.
4.	Liu P, Wang Z, Ou X, et al. The FUS/circEZH2/KLF5/ feedback loop contributes to CXCR4-induced liver metastasis of breast cancer by enhancing epithelial-mesenchymal transition. Mol Cancer, 2022, 21(1): 198.
5.	Zou Y, Ye F, Kong Y, et al. The single-cell landscape of intratumoral heterogeneity and the immunosuppressive microenvironment in liver and brain metastases of breast cancer. Adv Sci (Weinh), 2023, 10(5): e2203699.
6.	Rodrigues-Ferreira S, Nahmias C. Predictive biomarkers for personalized medicine in breast cancer. Cancer Lett, 2022, 545: 215828.
7.	Scherbakov AM, Basharina AA, Sorokin DV, et al. Targeting hormone-resistant breast cancer cells with docetaxel: a look inside the resistance. Cancer Drug Resist, 2023, 6(1): 103-115.
8.	Wu S, Pan R, Lu J, et al. Development and verification of a prognostic ferroptosis-related gene model in triple-negative breast cancer. Front Oncol, 2022, 12: 896927.
9.	Yin Y, Yan Y, Fan B, et al. Novel combination therapy for triple-negative breast cancer based on an intelligent hollow carbon sphere. Research (Wash D C), 2023, 6: 0098.
10.	Lowe L, LaValley JW, Felsher DW. Tackling heterogeneity in treatment-resistant breast cancer using a broad-spectrum therapeutic approach. Cancer Drug Resist, 2022, 5(4): 917-925.
11.	Tang Y, Tian W, Zheng S, et al. Dissection of FOXO1-induced LYPLAL1-DT impeding triple-negative breast cancer progression via mediating hnRNPK/β-catenin complex. Research (Wash D C), 2023, 6: 0289.
12.	Zeng Y, Du W, Huang Z, et al. Hsa_circ_0060467 promotes breast cancer liver metastasis by complexing with eIF4A3 and sponging miR-1205. Cell Death Discov, 2023, 9(1): 153.
13.	Ji X, Tian X, Feng S, et al. Intermittent F-actin perturbations by magnetic fields inhibit breast cancer metastasis. Research (Wash D C), 2023, 6: 0080.
14.	Misir S, Yaman SO, Petrovi? N, et al. circRNAs in drug resistance of breast cancer. Oncol Res, 2022, 30(4): 157-172.
15.	Zhang Q, Zhang P, Li B, et al. The expression of perilipin family proteins can be used as diagnostic markers of liposarcoma and to differentiate subtypes. J Cancer, 2020, 11(14): 4081-4090.
16.	Townsend LK, McKie GL. Using PLIN proteins to explain the athlete’s paradox. J Physiol, 2017, 595(22): 6819-6820.
17.	Cho KY, Miyoshi H, Nakamura A, et al. Lipid droplet protein PLIN1 regulates inflammatory polarity in human macrophages and is involved in atherosclerotic plaque development by promoting stable lipid storage. J Atheroscler Thromb, 2023, 30(2): 170-181.
18.	Vergès B, Vantyghem MC, Reznik Y, et al. Hypertriglyceridemia results from an impaired catabolism of triglyceride-rich lipoproteins in PLIN1-related lipodystrophy. Arterioscler Thromb Vasc Biol, 2024, 44(8): 1873-1883.
19.	Lu C, Wang X, Zhao X, et al. Long non-coding RNA ARAP1-AS1 accelerates cell proliferation and migration in breast cancer through miR-2110/HDAC2/PLIN1 axis. Biosci Rep, 2020, 40(4): BSR20191764.
20.	Compton ML, Al-Rohil RN. The utility of perilipin in liposarcomas: PLIN1 differentiates round cell liposarcoma from other round cell sarcomas. Appl Immunohistochem Mol Morphol, 2021, 29(2): 152-157.
21.	Zhang X, Su L, Sun K. Expression status and prognostic value of the perilipin family of genes in breast cancer. Am J Transl Res, 2021, 13(5): 4450-4463.
22.	Tomczak K, Czerwińska P, Wiznerowicz M. The Cancer Genome Atlas (TCGA): an immeasurable source of knowledge. Contemp Oncol (Pozn), 2015, 19(1A): A68-A77.
23.	GTEx Consortium. The genotype-tissue expression (GTEx) project. Nat Genet, 2013, 45(6): 580-585.
24.	Pontén F, Jirstr?m K, Uhlen M. The human protein atlas--a tool for pathology. J Pathol, 2008, 216(4): 387-393.
25.	Jézéquel P, Frénel JS, Campion L, et al. bc-GenExMiner 3.0: new mining module computes breast cancer gene expression correlation analyses. Database (Oxford), 2013, 2013: bas060.
26.	Jézéquel P, Campone M, Gouraud W, et al. bc-GenExMiner: an easy-to-use online platform for gene prognostic analyses in breast cancer. Breast Cancer Res Treat, 2012, 131(3): 765-775.
27.	Chandrashekar DS, Bashel B, Balasubramanya SAH, et al. UALCAN: a portal for facilitating tumor subgroup gene expression and survival analyses. Neoplasia, 2017, 19(8): 649-658.
28.	Pencina MJ, D’Agostino RB Sr. Evaluating discrimination of risk prediction models: the c statistic. JAMA, 2015, 314(10): 1063-1064.
29.	Alba AC, Agoritsas T, Walsh M, et al. Discrimination and calibration of clinical prediction models: users’ guides to the medical literature. JAMA, 2017, 318(14): 1377-1384.
30.	Nagy á, Lánczky A, Menyhárt O, et al. Validation of miRNA prognostic power in hepatocellular carcinoma using expression data of independent datasets. Sci Rep, 2018, 8(1): 9227.
31.	Li W, Shih A, Freudenberg-Hua Y, et al. Beyond standard pipeline and p<0. 05 in pathway enrichment analyses. Comput Biol Chem, 2021, 92: 107455.
32.	Hung JH, Yang TH, Hu Z, et al. Gene set enrichment analysis: performance evaluation and usage guidelines. Brief Bioinform, 2012, 13(3): 281-291.
33.	Liu W, Liu X, Liu Y, et al. PLIN2 promotes HCC cells proliferation by inhibiting the degradation of HIF1α. Exp Cell Res, 2022, 418(1): 113244.
34.	Shi GJ, Zhou Q, Zhu Q, et al. A novel prognostic model associated with the overall survival in patients with breast cancer based on lipid metabolism-related long noncoding RNAs. J Clin Lab Anal, 2022, 36(6): e24384.
35.	Matsubara J, Honda K, Ono M, et al. Identification of adipophilin as a potential plasma biomarker for colorectal cancer using label-free quantitative mass spectrometry and protein microarray. Cancer Epidemiol Biomarkers Prev, 2011, 20(10): 2195-2203.
36.	Li J, Zhang Q, Guan Y, et al. TRIB3 promotes the progression of renal cell carcinoma by upregulating the lipid droplet-associated protein PLIN2. Cell Death Dis, 2024, 15(4): 240.
37.	Wang Q, Zhao J, Zhang M, et al. Neuroinvasive virus utilizes a lipid droplet surface protein, perilipin2, to restrict apoptosis by decreasing Bcl-2 ubiquitination. J Virol, 2024, 98(12): e0160724.
38.	Tang D, Zhao YC, Liu H, et al. Potentially functional genetic variants in PLIN2, SULT2A1 and UGT1A9 genes of the ketone pathway and survival of nonsmall cell lung cancer. Int J Cancer, 2020, 147(6): 1559-1570.
39.	Lin Y, Pu S, Wang J, et al. Pancreatic STAT5 activation promotes Kras^G12D-induced and inflammation-induced acinar-to-ductal metaplasia and pancreatic cancer. Gut, 2024, 73(11): 1831-1843.
40.	Yao D, Xia S, Jin C, et al. Feedback activation of GATA1/miR-885-5p/PLIN3 pathway decreases sunitinib sensitivity in clear cell renal cell carcinoma. Cell Cycle, 2020, 19(17): 2195-2206.
41.	Sirois I, Aguilar-Mahecha A, Lafleur J, et al. A unique morphological phenotype in chemoresistant triple-negative breast cancer reveals metabolic reprogramming and PLIN4 expression as a molecular vulnerability. Mol Cancer Res, 2019, 17(12): 2492-2507.
42.	Ethem ?, Hac?o?lu C. Effects of perilipin-5 on lipid metabolism and high-sensitivity cardiac troponin I. Rev Assoc Med Bras (1992), 2022, 68(8): 1011-1016.
43.	Ma SY, Sun KS, Zhang M, et al. Disruption of PLIN5 degradation by CMA causes lipid homeostasis imbalance in NAFLD. Liver Int, 2020, 40(10): 2427-2438.
44.	Jian L, Gao X, Wang C, et al. Perilipin 5 deficiency aggravates cardiac hypertrophy by stimulating lactate production in leptin-deficient mice. Biol Direct, 2023, 18(1): 54.
45.	Mass-Sanchez PB, Krizanac M, ?tancl P, et al. Perilipin 5 deletion protects against nonalcoholic fatty liver disease and hepatocellular carcinoma by modulating lipid metabolism and inflammatory responses. Cell Death Discov, 2024, 10(1): 94.

1. Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2024, 74(3): 229-263.
2. Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin, 2024, 74(1): 12-49.
3. Wang Z, Yang L, Wu P, et al. The circROBO1/KLF5/FUS feedback loop regulates the liver metastasis of breast cancer by inhibiting the selective autophagy of afadin. Mol Cancer, 2022, 21(1): 29.
4. Liu P, Wang Z, Ou X, et al. The FUS/circEZH2/KLF5/ feedback loop contributes to CXCR4-induced liver metastasis of breast cancer by enhancing epithelial-mesenchymal transition. Mol Cancer, 2022, 21(1): 198.
5. Zou Y, Ye F, Kong Y, et al. The single-cell landscape of intratumoral heterogeneity and the immunosuppressive microenvironment in liver and brain metastases of breast cancer. Adv Sci (Weinh), 2023, 10(5): e2203699.
6. Rodrigues-Ferreira S, Nahmias C. Predictive biomarkers for personalized medicine in breast cancer. Cancer Lett, 2022, 545: 215828.
7. Scherbakov AM, Basharina AA, Sorokin DV, et al. Targeting hormone-resistant breast cancer cells with docetaxel: a look inside the resistance. Cancer Drug Resist, 2023, 6(1): 103-115.
8. Wu S, Pan R, Lu J, et al. Development and verification of a prognostic ferroptosis-related gene model in triple-negative breast cancer. Front Oncol, 2022, 12: 896927.
9. Yin Y, Yan Y, Fan B, et al. Novel combination therapy for triple-negative breast cancer based on an intelligent hollow carbon sphere. Research (Wash D C), 2023, 6: 0098.
10. Lowe L, LaValley JW, Felsher DW. Tackling heterogeneity in treatment-resistant breast cancer using a broad-spectrum therapeutic approach. Cancer Drug Resist, 2022, 5(4): 917-925.
11. Tang Y, Tian W, Zheng S, et al. Dissection of FOXO1-induced LYPLAL1-DT impeding triple-negative breast cancer progression via mediating hnRNPK/β-catenin complex. Research (Wash D C), 2023, 6: 0289.
12. Zeng Y, Du W, Huang Z, et al. Hsa_circ_0060467 promotes breast cancer liver metastasis by complexing with eIF4A3 and sponging miR-1205. Cell Death Discov, 2023, 9(1): 153.
13. Ji X, Tian X, Feng S, et al. Intermittent F-actin perturbations by magnetic fields inhibit breast cancer metastasis. Research (Wash D C), 2023, 6: 0080.
14. Misir S, Yaman SO, Petrovi? N, et al. circRNAs in drug resistance of breast cancer. Oncol Res, 2022, 30(4): 157-172.
15. Zhang Q, Zhang P, Li B, et al. The expression of perilipin family proteins can be used as diagnostic markers of liposarcoma and to differentiate subtypes. J Cancer, 2020, 11(14): 4081-4090.
16. Townsend LK, McKie GL. Using PLIN proteins to explain the athlete’s paradox. J Physiol, 2017, 595(22): 6819-6820.
17. Cho KY, Miyoshi H, Nakamura A, et al. Lipid droplet protein PLIN1 regulates inflammatory polarity in human macrophages and is involved in atherosclerotic plaque development by promoting stable lipid storage. J Atheroscler Thromb, 2023, 30(2): 170-181.
18. Vergès B, Vantyghem MC, Reznik Y, et al. Hypertriglyceridemia results from an impaired catabolism of triglyceride-rich lipoproteins in PLIN1-related lipodystrophy. Arterioscler Thromb Vasc Biol, 2024, 44(8): 1873-1883.
19. Lu C, Wang X, Zhao X, et al. Long non-coding RNA ARAP1-AS1 accelerates cell proliferation and migration in breast cancer through miR-2110/HDAC2/PLIN1 axis. Biosci Rep, 2020, 40(4): BSR20191764.
20. Compton ML, Al-Rohil RN. The utility of perilipin in liposarcomas: PLIN1 differentiates round cell liposarcoma from other round cell sarcomas. Appl Immunohistochem Mol Morphol, 2021, 29(2): 152-157.
21. Zhang X, Su L, Sun K. Expression status and prognostic value of the perilipin family of genes in breast cancer. Am J Transl Res, 2021, 13(5): 4450-4463.
22. Tomczak K, Czerwińska P, Wiznerowicz M. The Cancer Genome Atlas (TCGA): an immeasurable source of knowledge. Contemp Oncol (Pozn), 2015, 19(1A): A68-A77.
23. GTEx Consortium. The genotype-tissue expression (GTEx) project. Nat Genet, 2013, 45(6): 580-585.
24. Pontén F, Jirstr?m K, Uhlen M. The human protein atlas--a tool for pathology. J Pathol, 2008, 216(4): 387-393.
25. Jézéquel P, Frénel JS, Campion L, et al. bc-GenExMiner 3.0: new mining module computes breast cancer gene expression correlation analyses. Database (Oxford), 2013, 2013: bas060.
26. Jézéquel P, Campone M, Gouraud W, et al. bc-GenExMiner: an easy-to-use online platform for gene prognostic analyses in breast cancer. Breast Cancer Res Treat, 2012, 131(3): 765-775.
27. Chandrashekar DS, Bashel B, Balasubramanya SAH, et al. UALCAN: a portal for facilitating tumor subgroup gene expression and survival analyses. Neoplasia, 2017, 19(8): 649-658.
28. Pencina MJ, D’Agostino RB Sr. Evaluating discrimination of risk prediction models: the c statistic. JAMA, 2015, 314(10): 1063-1064.
29. Alba AC, Agoritsas T, Walsh M, et al. Discrimination and calibration of clinical prediction models: users’ guides to the medical literature. JAMA, 2017, 318(14): 1377-1384.
30. Nagy á, Lánczky A, Menyhárt O, et al. Validation of miRNA prognostic power in hepatocellular carcinoma using expression data of independent datasets. Sci Rep, 2018, 8(1): 9227.
31. Li W, Shih A, Freudenberg-Hua Y, et al. Beyond standard pipeline and p<0. 05 in pathway enrichment analyses. Comput Biol Chem, 2021, 92: 107455.
32. Hung JH, Yang TH, Hu Z, et al. Gene set enrichment analysis: performance evaluation and usage guidelines. Brief Bioinform, 2012, 13(3): 281-291.
33. Liu W, Liu X, Liu Y, et al. PLIN2 promotes HCC cells proliferation by inhibiting the degradation of HIF1α. Exp Cell Res, 2022, 418(1): 113244.
34. Shi GJ, Zhou Q, Zhu Q, et al. A novel prognostic model associated with the overall survival in patients with breast cancer based on lipid metabolism-related long noncoding RNAs. J Clin Lab Anal, 2022, 36(6): e24384.
35. Matsubara J, Honda K, Ono M, et al. Identification of adipophilin as a potential plasma biomarker for colorectal cancer using label-free quantitative mass spectrometry and protein microarray. Cancer Epidemiol Biomarkers Prev, 2011, 20(10): 2195-2203.
36. Li J, Zhang Q, Guan Y, et al. TRIB3 promotes the progression of renal cell carcinoma by upregulating the lipid droplet-associated protein PLIN2. Cell Death Dis, 2024, 15(4): 240.
37. Wang Q, Zhao J, Zhang M, et al. Neuroinvasive virus utilizes a lipid droplet surface protein, perilipin2, to restrict apoptosis by decreasing Bcl-2 ubiquitination. J Virol, 2024, 98(12): e0160724.
38. Tang D, Zhao YC, Liu H, et al. Potentially functional genetic variants in PLIN2, SULT2A1 and UGT1A9 genes of the ketone pathway and survival of nonsmall cell lung cancer. Int J Cancer, 2020, 147(6): 1559-1570.
39. Lin Y, Pu S, Wang J, et al. Pancreatic STAT5 activation promotes Kras^G12D-induced and inflammation-induced acinar-to-ductal metaplasia and pancreatic cancer. Gut, 2024, 73(11): 1831-1843.
40. Yao D, Xia S, Jin C, et al. Feedback activation of GATA1/miR-885-5p/PLIN3 pathway decreases sunitinib sensitivity in clear cell renal cell carcinoma. Cell Cycle, 2020, 19(17): 2195-2206.
41. Sirois I, Aguilar-Mahecha A, Lafleur J, et al. A unique morphological phenotype in chemoresistant triple-negative breast cancer reveals metabolic reprogramming and PLIN4 expression as a molecular vulnerability. Mol Cancer Res, 2019, 17(12): 2492-2507.
42. Ethem ?, Hac?o?lu C. Effects of perilipin-5 on lipid metabolism and high-sensitivity cardiac troponin I. Rev Assoc Med Bras (1992), 2022, 68(8): 1011-1016.
43. Ma SY, Sun KS, Zhang M, et al. Disruption of PLIN5 degradation by CMA causes lipid homeostasis imbalance in NAFLD. Liver Int, 2020, 40(10): 2427-2438.
44. Jian L, Gao X, Wang C, et al. Perilipin 5 deficiency aggravates cardiac hypertrophy by stimulating lactate production in leptin-deficient mice. Biol Direct, 2023, 18(1): 54.
45. Mass-Sanchez PB, Krizanac M, ?tancl P, et al. Perilipin 5 deletion protects against nonalcoholic fatty liver disease and hepatocellular carcinoma by modulating lipid metabolism and inflammatory responses. Cell Death Discov, 2024, 10(1): 94.

West China Medical Journal

Analysis of PLIN gene family as prognostic biomarkers associated with immune infiltration in breast cancer

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