HSulf‑1 and palbociclib exert synergistic antitumor effects on RB‑positive triple‑negative breast cancer

Human sulfatase‑1 (HSulf‑1) is emerging as a novel prognostic biomarker in breast cancer. Previous studies demonstrated HSulf‑1 to function as a negative regulator of cyclin D1 in breast cancer. Accumulating preclinical evidence is supporting the efficacy of cyclin‑dependent kinase (CDK) 4/6 inhibitors against the luminal androgen receptor sub‑type of triple‑negative breast cancer (TNBC). It was therefore hypothesized that HSulf‑1 may cooperate with CDK4/6 inhibitors to control cell cycle progression in breast cancer cells. HSulf‑1 expression was found to be downregulated in TNBC tissues and cell lines compared with that in healthy tissues and non‑breast cancer cell lines, respectively. High levels of HSulf‑1 expression was also found to be associated with increased progression‑free survival and overall survival in patients with TNBC. Functionally, it was demonstrated that HSulf‑1 served as tumor suppressor in TNBC by inducing cell cycle arrest and apoptosis whilst inhibiting proliferation, epithelial‑mesenchymal transition, migration and invasion. Subsequent overexpression of HSulf‑1 coupled with treatment with the CDK4/6 inhibitor palbociclib exhibited a synergistic antitumor effect on retinoblastoma (RB)‑positive TNBC. Further studies revealed the mechanism underlying this cooperative antiproliferative effect involved to be due to the prohibitive effects of HSulf‑1 on the palbociclib‑induced accumulation of cyclin D1 through AKT/STAT3 and ERK1/2/STAT3 signaling. Taken together, findings from the present study not only suggest that HSulf‑1 may be a potential therapeutic target for TNBC, but also indicate that combinatorial treatment could be an alternative therapeutic option for RB‑positive TNBC, which may open novel perspectives.