Targeting p70S6K1 Inhibits Glycated Albumin-Induced Triple-Negative Breast Cancer Cell Invasion and Overexpression of Galectin-3, a Potential Prognostic Marker in Diabetic Patients with Invasive Breast Cancer.

Background: There is an urgent need to identify new biomarkers for early diagnosis and development of therapeutic strategies for diabetes mellitus (DM) patients who have invasive breast cancer (BC). We previously reported the increased activated form of 70 kDa ribosomal protein S6 kinase 1 (phospho-p70S6K1) in a triple-negative BC (TNBC) cell line MDA-MB-231 exposed to glycated albumin (GA) and in invasive ductal carcinoma tissues from T2DM patients, compared to untreated cells and their non-diabetic counterparts, respectively. Objective: We aimed to explore the function of p70S6K1 in GA-promoted TNBC progression. Methods: By employing small interference (si)RNA technology or blocking its kinase activity using its specific pharmacological inhibitor, we monitored cell invasion using Transwell(®) inserts and the expression levels of activated signaling proteins and cancer-related proteins using Western blot. Results: In silico analysis revealed that high mRNA levels of p70S6K1 were associated with an unfavorable prognosis and progression to advanced stages of TNBC in DM patients. The downregulation/blockade of p70S6K1 inhibited GA-promoted MDA-MB-231 cell invasion and the phosphorylation of protein S6 and ERK1/2, the p70S6K1 downstream effector, and the key oncogenic signaling protein, respectively. The suppression of the expression of GA-upregulated cancer proteins, including enolase-2, capping protein CapG, galectin-3, and cathepsin D, was observed after p70S6K1 downregulation/blockade. Further in silico validation analyses revealed increased gene expression of galectin-3 in DM TNBC patients, resulting in poor overall survival and disease-free survival. Conclusions: Targeting p70S6K1 may present a valuable therapeutic strategy, while galectin-3 could serve as a potential prognostic biomarker for invasive BC progression in DM patients.