Squalene epoxidase expression is associated with breast tumor progression and with a poor prognosis in breast cancer

Kim,Nah Ihm; Park,Min Ho; Kweon,Sun-Seog; Cho,Namki; Lee,Ji Shin

doi:10.3892/ol.2021.12520

Squalene epoxidase expression is associated with breast tumor progression and with a poor prognosis in breast cancer

Authors:
- Nah Ihm Kim
- Min Ho Park
- Sun-Seog Kweon
- Namki Cho
- Ji Shin Lee
View Affiliations

Affiliations: Department of Pathology, Chonnam National University Medical School, Gwangju 61469, Republic of Korea, Department of Surgery, Chonnam National University Medical School, Gwangju 61469, Republic of Korea, Department of Preventive Medicine, Chonnam National University Medical School, Gwangju 61469, Republic of Korea, College of Pharmacy, Chonnam National University, Gwangju 61186, Republic of Korea
Published online on: February 4, 2021 https://doi.org/10.3892/ol.2021.12520
Article Number: 259
Copyright: © Kim et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Differentially expressed genes (DEGs) have been previously identified using massive parallel RNA sequencing in matched normal, breast cancer (BC) and nodal metastatic tissues. Squalene epoxidase (SQLE), one of these DEGs, is a key enzyme in cholesterol synthesis. The aim of the present study was to investigate the potential involvement of SQLE in the tumorigenic process of BC and to determine its association with the clinical outcome of BC. SQLE mRNA expression was measured using reverse transcription‑quantitative PCR in 10 pairs of ductal carcinoma in situ (DCIS) and BC tissues and their adjacent normal tissues. Immunohistochemical staining of SQLE on tissue microarray was performed in 26 normal breast, 79 DCIS and 198 BC samples. The role of SQLE as a prognostic biomarker in patients with BC has been verified using BreastMark. SQLE mRNA expression was significantly increased in DCIS and BC tissues compared with that in their adjacent normal tissues. High SQLE expression was detected in 0, 48.1 and 40.4% of normal breast, DCIS and BC tissues, respectively. SQLE expression in DCIS and BC tissues was significantly higher than that in normal breast tissues. High SQLE expression was observed in DCIS with higher nuclear grade, comedo‑type necrosis and HER2 positivity. High SQLE expression in BC was associated with larger tumor size, nodal metastases, higher stage, HER2 subtype and distant metastatic relapse. High SQLE expression was associated with poor disease‑free and overall survival, and independently predicted poor disease‑free survival in patients with BC. Following BreastMark analysis, high SQLE mRNA expression in BC was significantly associated with a poor prognosis in the ‘all’, lymph node negative, lymph node positive, luminal A subtype and luminal B subtype groups. Therefore, SQLE expression may be upregulated during the tumorigenic process of BC, and high SQLE expression may be a useful biomarker for predicting a poor prognosis in patients with BC.

View Figures

View References

1	Park EH, Min SY, Kim Z, Yoon CS, Jung KW, Nam SJ, Oh SJ, Lee S, Park BW, Lim W, et al Korean Breast Cancer Society, : Basic facts of breast cancer in Korea in 2014: The 10-year overall survival progress. J Breast Cancer. 20:1–11. 2017. View Article : Google Scholar : PubMed/NCBI
2	Akram M, Iqbal M, Daniyal M and Khan AU: Awareness and current knowledge of breast cancer. Biol Res. 50:332017. View Article : Google Scholar : PubMed/NCBI
3	Cirmena G, Franceschelli P, Isnaldi E, Ferrando L, De Mariano M, Ballestrero A and Zoppoli G: Squalene epoxidase as a promising metabolic target in cancer treatment. Cancer Lett. 425:13–20. 2018. View Article : Google Scholar : PubMed/NCBI
4	Silvente-Poirot S and Poirot M: Cholesterol metabolism and cancer: The good, the bad and the ugly. Curr Opin Pharmacol. 12:673–676. 2012. View Article : Google Scholar : PubMed/NCBI
5	Hu J, Locasale JW, Bielas JH, O'Sullivan J, Sheahan K, Cantley LC, Vander Heiden MG and Vitkup D: Heterogeneity of tumor-induced gene expression changes in the human metabolic network. Nat Biotechnol. 31:522–529. 2013. View Article : Google Scholar : PubMed/NCBI
6	Silvente-Poirot S and Poirot M: Cancer. Cholesterol and cancer, in the balance. Science. 343:1445–1446. 2014. View Article : Google Scholar : PubMed/NCBI
7	Silvente-Poirot S and Poirot M: Cholesterol epoxide hydrolase and cancer. Curr Opin Pharmacol. 12:696–703. 2012. View Article : Google Scholar : PubMed/NCBI
8	Nagai M, Sakakibara J, Wakui K, Fukushima Y, Igarashi S, Tsuji S, Arakawa M and Ono T; Nagai M1, ; Sakakibara J, Wakui K, Fukushima Y, Igarashi S, Tsuji S, Arakawa M and Ono T: Localization of the squalene epoxidase gene (SQLE) to human chromosome region 8q24.1. Genomics. 44:141–143. 1997. View Article : Google Scholar : PubMed/NCBI
9	Stopsack KH, Gerke TA, Sinnott JA, Penney KL, Tyekucheva S, Sesso HD, Andersson SO, Andrén O, Cerhan JR, Giovannucci EL, et al: Cholesterol metabolism and prostate cancer lethality. Cancer Res. 76:4785–4790. 2016. View Article : Google Scholar : PubMed/NCBI
10	Stopsack KH, Gerke TA, Andrén O, Andersson SO, Giovannucci EL, Mucci LA and Rider JR: Cholesterol uptake and regulation in high-grade and lethal prostate cancers. Carcinogenesis. 38:806–811. 2017. View Article : Google Scholar : PubMed/NCBI
11	Liu D, Wong CC, Fu L, Chen H, Zhao L, Li C, Zhou Y, Zhang Y, Xu W, Yang Y, et al: Squalene epoxidase drives NAFLD-induced hepatocellular carcinoma and is a pharmaceutical target. Sci Transl Med. 10:4372018. View Article : Google Scholar
12	Souchek JJ, Baine MJ, Lin C, Rachagani S, Gupta S, Kaur S, Lester K, Zheng D, Chen S, Smith L, et al: Unbiased analysis of pancreatic cancer radiation resistance reveals cholesterol biosynthesis as a novel target for radiosensitisation. Br J Cancer. 111:1139–1149. 2014. View Article : Google Scholar : PubMed/NCBI
13	Qin Y, Zhang Y, Tang Q, Jin L and Chen Y: SQLE induces epithelial-to-mesenchymal transition by regulating of miR-133b in esophageal squamous cell carcinoma. Acta Biochim Biophys Sin (Shanghai). 49:138–148. 2017.PubMed/NCBI
14	Zhang HY, Li HM, Yu Z, Yu XY and Guo K: Expression and significance of squalene epoxidase in squamous lung cancerous tissues and pericarcinoma tissues. Thorac Cancer. 5:275–280. 2014. View Article : Google Scholar : PubMed/NCBI
15	Römer AM, Lühr I, Klein A, Friedl A, Sebens S, Rösel F, Arnold N, Strauss A, Jonat W and Bauer M: Normal mammary fibroblasts induce reversion of the malignant phenotype in human primary breast cancer. Anticancer Res. 33:1525–1536. 2013.PubMed/NCBI
16	Polycarpou-Schwarz M, Gross M, Mestdagh P, Schott J, Grund SE, Hildenbrand C, Rom J, Aulmann S, Sinn HP, Vandesompele J, et al: The cancer-associated microprotein CASIMO1 controls cell proliferation and interacts with squalene epoxidase modulating lipid droplet formation. Oncogene. 37:4750–4768. 2018. View Article : Google Scholar : PubMed/NCBI
17	Helms MW, Kemming D, Pospisil H, Vogt U, Buerger H, Korsching E, Liedtke C, Schlotter CM, Wang A, Chan SY, et al: Squalene epoxidase, located on chromosome 8q24.1, is upregulated in 8q+ breast cancer and indicates poor clinical outcome in stage I and II disease. Br J Cancer. 99:774–780. 2008. View Article : Google Scholar : PubMed/NCBI
18	Yu Z, He Q and Xu G: Screening of prognostic factors in early-onset breast cancer. Technol Cancer Res Treat. Feb 7–2020.(Epub ahead of print). doi: 10.1177/1533033819893670. View Article : Google Scholar
19	D'Arcy M, Fleming J, Robinson WR, Kirk EL, Perou CM and Troester MA: Race-associated biological differences among Luminal A breast tumors. Breast Cancer Res Treat. 152:437–448. 2015. View Article : Google Scholar : PubMed/NCBI
20	Simigdala N, Gao Q, Pancholi S, Roberg-Larsen H, Zvelebil M, Ribas R, Folkerd E, Thompson A, Bhamra A, Dowsett M, et al: Cholesterol biosynthesis pathway as a novel mechanism of resistance to estrogen deprivation in estrogen receptor-positive breast cancer. Breast Cancer Res. 18:582016. View Article : Google Scholar : PubMed/NCBI
21	Kim S, Kon M and DeLisi C: Pathway-based classification of cancer subtypes. Biol Direct. 7:212012. View Article : Google Scholar : PubMed/NCBI
22	Shkurnikov MY, Galatenko VV, Lebedev AE, Podol'skii VE, Tonevitskii EA and Mal'tseva DV: On statistical relationship between ADRA2A expression and the risk of breast cancer relapse. Bull Exp Biol Med. 157:454–458. 2014. View Article : Google Scholar : PubMed/NCBI
23	Parada H Jr, Sun X, Fleming JM, Williams-DeVane CR, Kirk EL, Olsson LT, Perou CM, Olshan AF and Troester MA: Race-associated biological differences among luminal A and basal-like breast cancers in the Carolina Breast Cancer Study. Breast Cancer Res. 19:1312017. View Article : Google Scholar : PubMed/NCBI
24	Chin SF, Teschendorff AE, Marioni JC, Wang Y, Barbosa-Morais NL, Thorne NP, Costa JL, Pinder SE, van de Wiel MA, Green AR, et al: High-resolution aCGH and expression profiling identifies a novel genomic subtype of ER negative breast cancer. Genome Biol. 8:R2152007. View Article : Google Scholar : PubMed/NCBI
25	Parris TZ, Kovács A, Hajizadeh S, Nemes S, Semaan M, Levin M, Karlsson P and Helou K: Frequent MYC coamplification and DNA hypomethylation of multiple genes on 8q in 8p11-p12-amplified breast carcinomas. Oncogenesis. 3:e952014. View Article : Google Scholar : PubMed/NCBI
26	Brown DN, Caffa I, Cirmena G, Piras D, Garuti A, Gallo M, Alberti S, Nencioni A, Ballestrero A and Zoppoli G: Squalene epoxidase is a bona fide oncogene by amplification with clinical relevance in breast cancer. Sci Rep. 6:194352016. View Article : Google Scholar : PubMed/NCBI
27	Schnitt SJ, Allred C, Britton P, Ellis IO, Lakhani SR, Morrow M, Palazzo J, Reynolds C, Rutgers E, Simpson J, et al: Ductal carcinoma in situ. WHO Classification of Tumours of the Breast. Lakhani SR, Ellis IO, Tan PH and van de Vijver MJ: IARC Press; Lyon: pp. 90–94. 2012
28	Kim GE, Kim NI, Lee JS, Park MH and Kang K: Differentially expressed genes in matched normal, cancer, and lymph node metastases predict clinical outcomes in patients with breast cancer. Appl Immunohistochem Mol Morphol. 28:111–122. 2020. View Article : Google Scholar : PubMed/NCBI
29	Madden SF, Clarke C, Gaule P, Aherne ST, O'Donovan N, Clynes M, Crown J and Gallagher WM: BreastMark: An integrated approach to mining publicly available transcriptomic datasets relating to breast cancer outcome. Breast Cancer Res. 15:R522013. View Article : Google Scholar : PubMed/NCBI
30	Xu YF, Yi Y, Qiu SJ, Gao Q, Li YW, Dai CX, Cai MY, Ju MJ, Zhou J, Zhang BH, et al: PEBP1 downregulation is associated to poor prognosis in HCC related to hepatitis B infection. J Hepatol. 53:872–879. 2010. View Article : Google Scholar : PubMed/NCBI
31	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−ΔΔC(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
32	Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, Fitzgibbons PL, Francis G, Goldstein NS, Hayes M, et al: American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. Arch Pathol Lab Med. 134:907–922. 2010.PubMed/NCBI
33	Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, Cote RJ, Dowsett M, Fitzgibbons PL, Hanna WM, Langer A, et al American Society of Clinical Oncology; College of American Pathologists, : American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol. 25:118–145. 2007. View Article : Google Scholar : PubMed/NCBI
34	Bae YK, Gong G, Kang J, Lee A, Cho EY, Lee JS, Suh KS, Lee DW and Jung WH; Breast Pathology Study Group of Korean Society of Pathologists, : HER2 status by standardized immunohistochemistry and silver-enhanced in situ hybridization in Korean breast cancer. J Breast Cancer. 15:381–387. 2012. View Article : Google Scholar : PubMed/NCBI
35	Kim GE, Kim JH, Lee KH, Choi YD, Lee JS, Lee JH, Nam JH, Choi C, Park MH and Yoon JH: Stromal matrix metalloproteinase-14 expression correlates with the grade and biological behavior of mammary phyllodes tumors. Appl Immunohistochem Mol Morphol. 20:298–303. 2012. View Article : Google Scholar : PubMed/NCBI
36	Jardel P, Debiais C, Godet J, Irani J and Fromont G: Ductal carcinoma of the prostate shows a different immunophenotype from high grade acinar cancer. Histopathology. 63:57–63. 2013. View Article : Google Scholar : PubMed/NCBI
37	Kozera B and Rapacz M: Reference genes in real-time PCR. J Appl Genet. 54:391–406. 2013. View Article : Google Scholar : PubMed/NCBI