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.