Steroidogenic acute regulatory protein-related lipid transfer 4 (StarD4) promotes breast cancer cell proliferation and its mechanism_Journal of Biomedical Engineering

Authors：

HUANG Teng ¹ , SHAN Rong ¹ , ZHANG Min ¹ , LI Ling ² , HUANG Juan ³ , LIU Baoan ⁴ ,  ZHOU Weibing ¹

1. Department of Oncology, Xiangya Hospital, Central South University, Changsha 410008, P.R.China;
2. Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha 410008, P.R.China;
3. Hunan Province Clinic Meditech Research Center for Breast Cancer, Xiangya Hospital, Central South University, Changsha 410008, P.R.China;
4. Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, P.R.China;

Corresponding author：

ZHOU Weibing, Email: zhouweibing298@csu.edu.cn

Keywords：

triple negative breast cancer; StarD4; cholesterol metabolism; ITGA5

DOI：

10.7507/1001-5515.202105008

Video：

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Abstract Full text Figures/Tables Video References Cited by

Oncogene StarD4 had the function of promoting proliferation and metastasis of triple-negative breast cancer (TNBC), but its clinical value and molecular mechanism are unknown. This paper found that StarD4 was highly expressed in cancer tissues of TNBC patients, and higher expression level of StarD4 in TNBC patient resulted in poorer prognosis. Based on transcriptomics of MDA-MB-231 cell model, the results of bioinformatics analysis showed that down-regulated expression level of StarD4 led to overall downregulation of cholesterol-relative genes and significant enrichment of cancer mechanism and pathway. Further analysis and investigation verified that StarD4 might cross-promote the protein stability of receptor ITGA5 through the cholesterol pathway to enhance TNBC progression, which provides guidance for clinical application of TNBC diagnosis and treatment.

Citation： HUANG Teng, SHAN Rong, ZHANG Min, LI Ling, HUANG Juan, LIU Baoan, ZHOU Weibing. Steroidogenic acute regulatory protein-related lipid transfer 4 (StarD4) promotes breast cancer cell proliferation and its mechanism. Journal of Biomedical Engineering, 2021, 38(6): 1118-1125. doi: 10.7507/1001-5515.202105008 Copy

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17.	Zhang M, Xiang Z, Wang F, et al. STARD4 promotes breast cancer cell malignancy. Oncol Rep, 2020, 44(6): 2487-2502.
18.	Iaea D B, Mao S, Lund F W, et al. Role of STARD4 in sterol transport between the endocytic recycling compartment and the plasma membrane. Mol Biol Cell, 2017, 28(8): 1111-1122.
19.	Calderon-Dominguez M, Gil G, Medina M A, et al. The StarD4 subfamily of steroidogenic acute regulatory-related lipid transfer (START) domain proteins: New players in cholesterol metabolism. Int J Biochem Cell B, 2014, 49: 64-68.
20.	Shen M, Jiang Y Z, Wei Y, et al. Tinagl1 suppresses triple-negative breast cancer progression and metastasis by simultaneously inhibiting Integrin/FAK and EGFR signaling. Cancer Cell, 2019, 35(1): 64-80.
21.	Xiao Y, Li Y, Tao H, et al. Integrin α5 down-regulation by miR-205 suppresses triple negative breast cancer stemness and metastasis by inhibiting the Src/Vav2/Rac1 pathway. Cancer Lett, 2018, 433: 199-209.
22.	Chandrashekar D S, Bashel B, Balasubramanya S A H, et al. UALCAN: a portal for facilitating tumor subgroup gene expression and survival analyses. Neoplasia, 2017, 19(8): 649-658.
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24.	Sukhanova A, Gorin A, Serebriiskii I G, et al. Targeting C4-demethylating genes in the cholesterol pathway sensitizes cancer cells to EGF receptor inhibitors via increased EGF receptor degradation. Cancer Discov, 2013, 3(1): 96-111.
25.	Luo J, Yang H, Song B L. Mechanisms and regulation of cholesterol homeostasis. Nat Rev Mol Cell Bio, 2020, 21(4): 225-245.
26.	Liu X, Taftaf R, Kawaguchi M, et al. Homophilic CD44 interactions mediate tumor cell aggregation and polyclonal metastasis in patient-derived breast cancer models. Cancer Discov, 2018, 9(1): 96-113.
27.	Gomes A P, Ilter D, Low V, et al. Dynamic incorporation of histone H3 variants into chromatin is essential for acquisition of aggressive traits and metastatic colonization. Cancer Cell, 2019, 36(4): 402-417.
28.	Plaks V, Kong N, Werb Z. The Cancer Stem Cell Niche: How essential is the niche in regulating stemness of tumor cells?. Cell Stem Cell, 2015, 16(3): 225-238.
29.	Hamidi H, Ivaska J. Every step of the way: integrins in cancer progression and metastasis. Nat Rev Cancer, 2018, 18(9): 533-548.

1. Chen W, Zheng R, Baade P, et al. Cancer statistics in China, 2015. CA-Cancer J Clin, 2016, 66(2): 115-132.
2. Jiang Y, Ma D, Suo C, et al. Genomic and transcriptomic landscape of triple-negative breast cancers: subtypes and treatment strategies. Cancer cell, 2019, 35(3): 428-440.
3. Denkert C, Liedtke C, Tutt A, et al. Molecular alterations in triple-negative breast cancer-the road to new treatment strategies. Lancet, 2017, 389(10087): 2430-2442.
4. Wang Z, Chen J, Zhong M Z, et al. Overexpression of ANLN contributed to poor prognosis of anthracycline-based chemotherapy in breast cancer patients. Cancer Chemoth Pharm, 2017, 79(3): 1-9.
5. Garrido-Castro A, Lin N, Polyak K. Insights into molecular classifications of triple-negative breast cancer: improving patient selection for treatment. Cancer Discov, 2019, 9(2): 176-198.
6. Zhu J, Thompson C. Metabolic regulation of cell growth and proliferation. Nat Rev Mol Cell Bio, 2019, 20(7): 436-450.
7. Kamphorst J, Gottlieb E. Cancer metabolism: friendly neighbours feed tumour cells. Nature, 2016, 536(7617): 401-402.
8. Wagner E, Petruzzelli M. Cancer metabolism: A waste of insulin interference. Nature, 2015, 521(7553): 430-431.
9. Tasselli L, Chua K. Cancer: metabolism in 'the driver's seat. Nature, 2012, 492(7429): 362-363.
10. Cao Y. Adipocyte and lipid metabolism in cancer drug resistance. J Clin Invest, 2019, 129(8): 3006-3017.
11. Yang W, Bai Y, Xiong Y, et al. Potentiating the antitumour response of CD8⁺ T cells by modulating cholesterol metabolism. Nature, 2016, 531(7596): 651-655.
12. Ma X, Bi E, Lu Y, et al. Cholesterol induces CD8⁺ T cell exhaustion in the tumor microenvironment. Cell Metab, 2019, 30(1): 143-156.
13. Ehmsen S, Pedersen M H, Wang G, et al. Increased cholesterol biosynthesis is a key characteristic of breast cancer stem cells influencing patient outcome. Cell Rep, 2019, 27(13): 3927-3938.
14. Jiang Y, Sun A, Zhao Y, et al. Proteomics identifies new therapeutic targets of early-stage hepatocellular carcinoma. Nature, 2019, 567(7747): 257-261.
15. Gruosso T, Gigoux M, Vsk M, et al. Spatially distinct tumor immune microenvironments stratify triple-negative breast cancers. J Clin Invest, 2019, 129: 1785-1800.
16. Soccio R E. The STARD4 subfamily: STARD4 and STARD5 in cholesterol metabolism// Clark B J, Stocco D M. Cholesterol transporters of the START domain protein family in health and disease. New York: Springer, 2015: 139-171.
17. Zhang M, Xiang Z, Wang F, et al. STARD4 promotes breast cancer cell malignancy. Oncol Rep, 2020, 44(6): 2487-2502.
18. Iaea D B, Mao S, Lund F W, et al. Role of STARD4 in sterol transport between the endocytic recycling compartment and the plasma membrane. Mol Biol Cell, 2017, 28(8): 1111-1122.
19. Calderon-Dominguez M, Gil G, Medina M A, et al. The StarD4 subfamily of steroidogenic acute regulatory-related lipid transfer (START) domain proteins: New players in cholesterol metabolism. Int J Biochem Cell B, 2014, 49: 64-68.
20. Shen M, Jiang Y Z, Wei Y, et al. Tinagl1 suppresses triple-negative breast cancer progression and metastasis by simultaneously inhibiting Integrin/FAK and EGFR signaling. Cancer Cell, 2019, 35(1): 64-80.
21. Xiao Y, Li Y, Tao H, et al. Integrin α5 down-regulation by miR-205 suppresses triple negative breast cancer stemness and metastasis by inhibiting the Src/Vav2/Rac1 pathway. Cancer Lett, 2018, 433: 199-209.
22. Chandrashekar D S, Bashel B, Balasubramanya S A H, et al. UALCAN: a portal for facilitating tumor subgroup gene expression and survival analyses. Neoplasia, 2017, 19(8): 649-658.
23. Yu R, Longo J, Van Leeuwen J, et al. Statin-induced cancer cell death can be mechanistically uncoupled from prenylation of RAS family proteins. Cancer Res, 2018, 78(5): 1347-1357.
24. Sukhanova A, Gorin A, Serebriiskii I G, et al. Targeting C4-demethylating genes in the cholesterol pathway sensitizes cancer cells to EGF receptor inhibitors via increased EGF receptor degradation. Cancer Discov, 2013, 3(1): 96-111.
25. Luo J, Yang H, Song B L. Mechanisms and regulation of cholesterol homeostasis. Nat Rev Mol Cell Bio, 2020, 21(4): 225-245.
26. Liu X, Taftaf R, Kawaguchi M, et al. Homophilic CD44 interactions mediate tumor cell aggregation and polyclonal metastasis in patient-derived breast cancer models. Cancer Discov, 2018, 9(1): 96-113.
27. Gomes A P, Ilter D, Low V, et al. Dynamic incorporation of histone H3 variants into chromatin is essential for acquisition of aggressive traits and metastatic colonization. Cancer Cell, 2019, 36(4): 402-417.
28. Plaks V, Kong N, Werb Z. The Cancer Stem Cell Niche: How essential is the niche in regulating stemness of tumor cells?. Cell Stem Cell, 2015, 16(3): 225-238.
29. Hamidi H, Ivaska J. Every step of the way: integrins in cancer progression and metastasis. Nat Rev Cancer, 2018, 18(9): 533-548.

Journal of Biomedical Engineering

Steroidogenic acute regulatory protein-related lipid transfer 4 (StarD4) promotes breast cancer cell proliferation and its mechanism

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