Rong Li ¹, Qian Geng ², Rongcheng Luo ²

¹ Department of Oncology, Southern Medical University NanfangHospital, Guangzhou.

² Department of Oncology, TCM-Integrated Cancer Center of SouthernMedical University, Guangzhou.

Objective：Toexaminethe prognostic significance of SHP-1 in breast cancer, its role in regulationofbreast cancer cell growth and metastasis, and the underlying mechanisms. Method：Specimensfrom 189 cases ofpatients with breast cancer, including 160 patientswith follow-upinformation, and 39 non-cancerous tissues were used to examine the expressionof SHP-1 and to analyzethe association between SHP-1 and patients’ overallsurvival by Kaplan–Meier and multivariate Coxregression analyses. A series ofin vitro and in vivo assays were performedto elucidate the effects of SHP-1 inbreast cancer cell proliferation and invasion. Confocalimmunofluorescence andGST-pull down assays were applied to demonstratethe interaction between SHP-1and epidermal growth factor receptor (EGFR), which was further verified bywestern blotting analysis, as well as its downstream pathway.Immunohistochemistry (IHC) was applied to investigate the clinical associationbetween SHP-1 and EGFR in human breast cancer specimens. Result：SHP-1was inversely correlatedwith tumor size and theexpression of HER2, butpositively correlated with patients’ survival,the expression of ER and PR.Ectopic SHP-1 expression significantly suppressed breast cancer cellproliferation, migration and invasion. On the contrary, SHP-1knockdown induceda more invasivephenotype and accelerated cell growth. Mechanistically, wediscovered EGFR as a direct interacting protein of SHP-1 and found thatEGFR/Ras/Erk/GSK3βsignaling pathway was inactivated. The downstream effectorssuch as β-catenin, cyclin D1, c-Myc, Snail andN-cadherin were downregulated, andE-cadherin was upregulated by SHP-1 overexpression. Moreover, EGFR was inverselycorrelated with SHP-1 in breast cancer specimens and predictedpoor prognosis ofpatients with breast cancer. Conclusion：SHP-1is an important prognostic biomarker inpatients with breast cancer and SHP-1-EGFRaxis is a promising target forbreast cancer therapy.

Key words：SHP-1   EGFR   breast cancer   proliferation   migration