Osteoglycin inhibits proliferation of Luminal breast cancer cells <i>via</i> up-regulating expression of estrogen receptor_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

ZHANG Rui , DU Qiuli , RUAN Jian ,  ZHAO Jianguo

Department of Thyroid and Breast Surgery, Wuhan No.1 Hospital, Wuhan 430030, P. R. China;

Corresponding author：

ZHAO Jianguo, Email: 3040114010@qq.com

Keywords：

Luminal breast cancer; Osteoglycin; estrogen receptor; proliferation

DOI：

10.7507/1007-9424.202106119

Video：

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Objective To investigate whether Osteoglycin (OGN) gene inhibits the proliferation of Luminal breast cancer cells by up-regulating the expression of estrogen receptor (ER). Methods ① Ualcan online database was used to analyze the expression of OGN in the breast cancer, and Kaplan-Meier Plotter was used to analyze the effect of OGN on the prognosis of patients with breast cancer. The median OGN mRNA expression level was taken as the cut-off point for high or low OGN expression. ② The expression of OGN mRNA in the Luminal breast cancer tissue of clinical case was examined using real time quantitative PCR (qRT-PCR). ③ Up-regulation of OGN expression in the Luminal breast cancer cell lines MCF-7 and T47D cells by transfection of overexpressing OGN plasmid, the expressions of OGN and ER were detected by qRT-PCR and Western blot, respectively. CCK8 assay and colony formation assay were applied to detect the cell proliferation and colony formation of Luminal breast cancer cells. ④ siRNA transfection was used to interfere with the expression of ER (ESR1) of breast cancer cells in the overexpressing OGN of breast cancer cells, then the CCK8 assay was used to detect the proliferation ability of the breast cancer cell lines after down-regulating the expression of ER in the overexpressing OGN patients. Results ① The results of Ualcan online database showed that the expression of OGN mRNA in the breast cancer tissues of different types of breast cancer was lower than that in the normal breast tissues (P<0.001), and which was highest in the Luminal breast cancer tissues (P<0.001). The Kaplan-Meier Plotter prognosis analysis showed that in all breast cancer or Luminal breast cancer patients, the prognosis of patients with high OGN expression was better than those with low OGN expression (P=0.000 14, P=0.001 80). ② The OGN mRNA expression was decreased in the 30 Luminal breast cancer samples as compared with the corresponding adjacent normal breast tissues (t=4.774, P=0.000 019). ③ The expressions of OGN and ER in the MCF-7 and T47D cells were up-regulated after transfection of overexpressing OGN plasmid (P=0.000 002, P=0.000 001). The cell proliferation was inhibited (P<0.05) and the number of cell clones was decreased significantly (P<0.05). ④ After transient transfection of siRNA interfered with breast cancer cell lines of overexpressing OGN, ER mRNA level decreased (P<0.05), and cell proliferation ability increased significantly (P<0.05). Conclusion OGN could exert a tumor suppressor effect in Luminal breast cancer by mediating expression of ER.

Citation： ZHANG Rui, DU Qiuli, RUAN Jian, ZHAO Jianguo. Osteoglycin inhibits proliferation of Luminal breast cancer cells via up-regulating expression of estrogen receptor. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2021, 28(12): 1580-1586. doi: 10.7507/1007-9424.202106119 Copy

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11.	刘敏, 谢巍伟, 郑维, 等. 雌二醇与ESR1靶向结合通过ERK信号通路调控软骨细胞的增殖. 南方医科大学学报, 2019, 39(2): 134-143.
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13.	Zhao J, Hu C, Wang C, et al. Breast cancer primary tumor ER expression pattern predicts its expression concordance in matched synchronous lymph node metastases. BMC Cancer, 2018, 18(1): 1290.
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15.	Hu X, Li YQ, Li QG, et al. Osteoglycin-induced VEGF inhibition enhances t lymphocytes infiltrating in colorectal cancer. EBioMedicine, 2018, 34: 35-45.
16.	Wassermann-Dozorets R, Rubinstein M. C/EBPβ LIP augments cell death by inducing osteoglycin. Cell Death Dis, 2017, 8(4): e2733.
17.	Saura C, Hlauschek D, Oliveira M, et al. Neoadjuvant letrozole plus taselisib versus letrozole plus placebo in postmenopausal women with oestrogen receptor-positive, HER2-negative, early-stage breast cancer (LORELEI): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol, 2019, 20(9): 1226-1238.
18.	覃绎, 袁洪范, 曾蓓蕾, 等. ATPIA2通过Src/PI3K/Akt信号通路抑制人乳腺癌细胞的侵袭和迁移. 第三军医大学学报, 2019, 41(22): 2166-2173.
19.	Kornblum N, Zhao F, Manola J, et al. Randomized phase Ⅱ trial of fulvestrant plus everolimus or placebo in postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer resistant to aromatase inhibitor therapy: results of PrE0102. J Clin Oncol, 2018, 36(16): 1556-1563.
20.	André F, Ciruelos E, Rubovszky G, et al. Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer. N Engl J Med, 2019, 380(20): 1929-1940.
21.	Toska E, Castel P, Chhangawala S, et al. PI3K inhibition activates SGK1 via a feedback loop to promote chromatin-based regulation of ER-dependent gene expression. Cell Rep, 2019, 27(1): 294-306.
22.	Castel P, Ellis H, Bago R, et al. PDK1-SGK1 signaling sustains AKT-independent mTORC1 activation and confers resistance to PI3Kα inhibition. Cancer Cell, 2016, 30(2): 229-242.
23.	Vasan N, Toska E, Scaltriti M. Overview of the relevance of PI3K pathway in HR-positive breast cancer. Ann Oncol, 2019, 30(Suppl_10): x3-x11.
24.	Alayev A, Salamon RS, Berger SM, et al. mTORC1 directly phosphorylates and activates ERα upon estrogen stimulation. Oncogene, 2016, 35(27): 3535-3543.
25.	Huang M, Wang Y. Roles of small gtpases in acquired tamoxifen resistance in MCF-7 cells revealed by targeted, quantitative proteomic analysis. Anal Chem, 2018, 90(24): 14551-14560.

1. Siegel RL, Miller KD, Fuchs HE, et al. Cancer statistics, 2021. CA Cancer J Clin, 2021, 71(1): 7-33.
2. Zhu Y, Liu Y, Zhang C, et al. Tamoxifen-resistant breast cancer cells are resistant to DNA-damaging chemotherapy because of upregulated BARD1 and BRCA1. Nat Commun, 2018, 9(1): 1595.
3. Kruger DT, Alexi X, Opdam M, et al. IGF-1R pathway activation as putative biomarker for linsitinib therapy to revert tamoxifen resistance in ER-positive breast cancer. Int J Cancer, 2020, 146(8): 2348-2359.
4. 时云, 王耕, 周坤, 等. Mdm2在ERα阳性乳腺癌组织中的表达及其siRNA对MCF-7细胞生物学行为的影响. 中国普外基础与临床杂志, 2016, 23(9): 1066-1072.
5. Jackisch C. Overcoming endocrine resistance in neoadjuvant endocrine therapy for early breast cancer. Lancet Oncol, 2019, 20(9): 1185-1187.
6. Fu B, Zhou Y, Ni X, et al. Natural killer cells promote fetal development through the secretion of growth-promoting factors. Immunity, 2017, 47(6): 1100-1113.
7. Tagliaferri C, Wittrant Y, Davicco MJ, et al. Muscle and bone, two interconnected tissues. Ageing Res Rev, 2015, 21: 55-70.
8. Casciello F, Al-Ejeh F, Kelly G, et al. G9a drives hypoxia-mediated gene repression for breast cancer cell survival and tumorigenesis. Proc Natl Acad Sci USA, 2017, 114(27): 7077-7082.
9. 潘秀华, 陈晓慧, 李晓青, 等. 骨诱导因子mRNA表达与乳腺癌发生和转移的关系. 天津医科大学学报, 2008, 14(2): 203-206.
10. Xu T, Zhang R, Dong M, et al. Osteoglycin (OGN) inhibits cell proliferation and invasiveness in breast cancer via PI3K/Akt/mTOR signaling pathway. Onco Targets Ther, 2019, 12: 10639-10650.
11. 刘敏, 谢巍伟, 郑维, 等. 雌二醇与ESR1靶向结合通过ERK信号通路调控软骨细胞的增殖. 南方医科大学学报, 2019, 39(2): 134-143.
12. DeSantis C, Ma J, Bryan L, et al. Breast cancer statistics, 2013. CA Cancer J Clin, 2014, 64(1): 52-62.
13. Zhao J, Hu C, Wang C, et al. Breast cancer primary tumor ER expression pattern predicts its expression concordance in matched synchronous lymph node metastases. BMC Cancer, 2018, 18(1): 1290.
14. Hu X, Li YQ, Li QG, et al. Osteoglycin (OGN) reverses epithelial to mesenchymal transition and invasiveness in colorectal cancer via EGFR/Akt pathway. J Exp Clin Cancer Res, 2018, 37(1): 41.
15. Hu X, Li YQ, Li QG, et al. Osteoglycin-induced VEGF inhibition enhances t lymphocytes infiltrating in colorectal cancer. EBioMedicine, 2018, 34: 35-45.
16. Wassermann-Dozorets R, Rubinstein M. C/EBPβ LIP augments cell death by inducing osteoglycin. Cell Death Dis, 2017, 8(4): e2733.
17. Saura C, Hlauschek D, Oliveira M, et al. Neoadjuvant letrozole plus taselisib versus letrozole plus placebo in postmenopausal women with oestrogen receptor-positive, HER2-negative, early-stage breast cancer (LORELEI): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol, 2019, 20(9): 1226-1238.
18. 覃绎, 袁洪范, 曾蓓蕾, 等. ATPIA2通过Src/PI3K/Akt信号通路抑制人乳腺癌细胞的侵袭和迁移. 第三军医大学学报, 2019, 41(22): 2166-2173.
19. Kornblum N, Zhao F, Manola J, et al. Randomized phase Ⅱ trial of fulvestrant plus everolimus or placebo in postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer resistant to aromatase inhibitor therapy: results of PrE0102. J Clin Oncol, 2018, 36(16): 1556-1563.
20. André F, Ciruelos E, Rubovszky G, et al. Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer. N Engl J Med, 2019, 380(20): 1929-1940.
21. Toska E, Castel P, Chhangawala S, et al. PI3K inhibition activates SGK1 via a feedback loop to promote chromatin-based regulation of ER-dependent gene expression. Cell Rep, 2019, 27(1): 294-306.
22. Castel P, Ellis H, Bago R, et al. PDK1-SGK1 signaling sustains AKT-independent mTORC1 activation and confers resistance to PI3Kα inhibition. Cancer Cell, 2016, 30(2): 229-242.
23. Vasan N, Toska E, Scaltriti M. Overview of the relevance of PI3K pathway in HR-positive breast cancer. Ann Oncol, 2019, 30(Suppl_10): x3-x11.
24. Alayev A, Salamon RS, Berger SM, et al. mTORC1 directly phosphorylates and activates ERα upon estrogen stimulation. Oncogene, 2016, 35(27): 3535-3543.
25. Huang M, Wang Y. Roles of small gtpases in acquired tamoxifen resistance in MCF-7 cells revealed by targeted, quantitative proteomic analysis. Anal Chem, 2018, 90(24): 14551-14560.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Osteoglycin inhibits proliferation of Luminal breast cancer cells via up-regulating expression of estrogen receptor

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