Downregulation of TSPAN1 inhibits angiogenesis in triple-negative breast cancer cells by regulating the PI3K/Akt signaling pathway

Background: Triple-negative breast cancer (TNBC) progression and invasion highly depends on abnormal angiogenesis. While tetraspanin 1 (TSPAN1) has been implicated in the malignant progression of TNBC, its relationship in tumor angiogenesis remains poorly understood. Methods: Tumor samples were collected from patients with TNBC and analyzed using clinical pathological and Western blot analyses. TSPAN1 expression was knocked down in the TNBC cell line, Hs-578T using siRNA technology. The angiogenic ability of human umbilical vein endothelial cells (HUVECs) was evaluated by lumen formation assay. The Phosphatidylinositol 3-Kinase (PI3K)/Protein Kinase B (Akt) signaling pathway was detected using western blots. Results: TSPAN1 overexpression in TNBC tumors is linked to metastasis and PI3K/Akt pathway activation. Knockdown of TSPAN1 in TNBC cells, significantly suppressed the tube formation ability of co-cultured HUVECs. Mechanistically, TSPAN1 knockdown significantly inhibited the activity of the PI3K/Akt pathway. Conclusions: In conclusion, TSPAN1 promotes TNBC angiogenesis via activation of PI3K/Akt signaling pathway.

Triple-negative breast cancer; TSPAN1; PI3K/Akt; Angiogenesis

[1] Li Y, Zhang H, Merkher Y, Chen L, Liu N, Leonov S, et al. Recent advances in therapeutic strategies for triple-negative breast cancer. Journal of Hematology & Oncology. 2022; 15: 121.

[2] Abbas MA, Al-Kabariti AY, Sutton C. Comprehensive understanding of the role of GPER in estrogen receptor-alpha negative breast cancer. The Journal of Steroid Biochemistry and Molecular Biology. 2024; 241: 106523.

[3] Adrada BE, Moseley TW, Kapoor MM, Scoggins ME, Patel MM, Perez F, et al. Triple-negative breast cancer: histopathologic features, genomics, and treatment. RadioGraphics. 2023; 43: e230034.

[4] Elayat G, Selim A. Angiogenesis in breast cancer: insights and innovations. Clinical and Experimental Medicine. 2024; 24: 178.

[5] de Heer EC, Jalving M, Harris AL. HIFs, angiogenesis, and metabolism: elusive enemies in breast cancer. Journal of Clinical Investigation. 2020; 130: 5074–5087.

[6] Richardson MM, Jennings LK, Zhang XA. Tetraspanins and tumor progression. Clinical & Experimental Metastasis. 2011; 28: 261–270.

[7] Wang MD, Li HT, Peng LX, Mei Y, Zheng LS, Li CZ, et al. TSPAN1 inhibits metastasis of nasopharyngeal carcinoma via suppressing NF-kB signaling. Cancer Gene Therapy. 2024; 31: 454–463.

[8] Huang H, Li H, Zhao T, Khan AA, Pan R, Wang S, et al. TSPAN1-elevated FAM110A promotes pancreatic cancer progression by transcriptionally regulating HIST1H2BK. Journal of Cancer. 2022; 13: 906–917.

[9] Han J, Xie C, Liu B, Wang Y, Pang R, Bi W, et al. Tetraspanin 1 regulates papillary thyroid tumor growth and metastasis through c-Myc-mediated glycolysis. Cancer Science. 2023; 114: 4535–4547.

[10] Wu Y, Chen W, Gong Y, Liu H, Zhang B. Tetraspanin 1 (TSPAN1) promotes growth and transferation of breast cancer cells via mediating PI3K/Akt pathway. Bioengineered. 2021; 12: 10761–10770.

[11] Cai Y, Zheng M, Zhao Z, Huang H, Fu W, Xu X. Expression of Tspan-1 gene in patients with advanced gastric cancer. Oncology Letters. 2017; 14: 2996–3000.

[12] Wang Y, Liang Y, Yang G, Lan Y, Han J, Wang J, et al. Tetraspanin 1 promotes epithelial-to-mesenchymal transition and metastasis of cholangiocarcinoma via PI3K/Akt signaling. Journal of Experimental & Clinical Cancer Research. 2018; 37: 300.

[13] Hinz N, Jucker M. Distinct functions of Akt isoforms in breast cancer: a comprehensive review. Cell Communication and Signaling. 2019; 17: 154.

[14] Zhang HP, Jiang RY, Zhu JY, Sun KN, Huang Y, Zhou HH, et al. PI3K/Akt/mTOR signaling pathway: an important driver and therapeutic target in triple-negative breast cancer. Breast Cancer. 2024; 31: 539–551.

[15] Huang R, Sun H, Lin R, Zhang J, Yin H, Xian S, et al. The role of tetraspanins pan-cancer. iScience. 2022; 25: 104777.

[16] Yousefi T, Mohammadi Jobani B, Taebi R, Qujeq D. Innovating cancer treatment through cell cycle, telomerase, angiogenesis, and metastasis. DNA and Cell Biology. 2024; 43: 438–451.

[17] Guo X, Yang Y, Tang J, Xiang J. Ephs in cancer progression: complexity and context-dependent nature in signaling, angiogenesis and immunity. Cell Communication and Signaling. 2024; 22: 299.

[18] Deryugina EI, Quigley JP. Tumor angiogenesis: MMP-mediated induction of intravasation- and metastasis-sustaining neovasculature. Matrix Biology. 2015; 44–46: 94–112.

[19] Li L, Fan P, Chou H, Li J, Wang K, Li H. Herbacetin suppressed MMP9 mediated angiogenesis of malignant melanoma through blocking EGFR-ERK/Akt signaling pathway. Biochimie. 2019; 162: 198–207.

[20] Wang T, Chen S, Wang Z, Li S, Fei X, Wang T, et al. KIRREL promotes the proliferation of gastric cancer cells and angiogenesis through the PI3K/Akt/mTOR pathway. Journal of Cellular and Molecular Medicine. 2024; 28: e18020.

[21] Jiang BH, Liu LZ. PI3K/PTEN signaling in angiogenesis and tumorigenesis. Advances in Cancer Research. 2009; 102: 19–65.