title: Chloroquine has tumor-inhibitory and tumor-promoting effects in triple-negative breast cancer.
abstract: Toll-like receptor-9 (TLR9) is an intracellular DNA receptor that is widely expressed in breast and other cancers. We previously demonstrated that low tumor TLR9 expression upon diagnosis is associated with significantly shortened disease-specific survival times in patients with triple-negative breast cancer (TNBC). There are no targeted therapies for this subgroup of patients whose prognosis is among the worst in breast cancer. Due to the previously detectedin vitroanti-invasive effects of chloroquine in these cell lines, the present study aimed to investigate thein vivoeffects of chloroquine against two clinical subtypes of TNBC that differ in TLR9 expression. Chloroquine suppressed matrix metalloproteinase (MMP)-2 and MMP-9 mRNA expression and protein activity, whereas MMP-13 mRNA expression and proteolytic activity were increased. Despite enhancing TLR9 mRNA expression, chloroquine suppressed TLR9 protein expressionin vitro. Daily treatment of mice with intraperitoneal (i.p.) chloroquine (80 mg/kg/day) for 22 days, did not inhibit the growth of control siRNA or TLR9 siRNA MDA-MB-231 breast cancer cells. In conclusion, despite the favorablein vitroeffects on TNBC invasion and viability, particularly in hypoxic conditions, chloroquine does not prevent the growth of the triple-negative MDA-MB-231 cells with high or low TLR9 expression levelsin vivo. This may be explained by the activating effects of chloroquine on MMP-13 expression or by the fact that chloroquine, by suppressing TLR9 expression, permits the activation of currently unknown molecular pathways, which allow the aggressive behavior of TNBC cells with low TLR9 expression in hypoxia.
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA ; MediCity/PET Preclinical Imaging, Turku PET Centre, University of Turku, Turku 20521, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Tuomela
authors.forename: Jouko
authors.initials: J
authors.lastname: Sandholm
authors.forename: Joonas H
authors.initials: JH
authors.lastname: Kauppila
authors.forename: Petri
authors.initials: P
authors.lastname: Lehenkari
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Harris
authors.forename: Katri S
authors.initials: KS
authors.lastname: Selander
keywords: chloroquine; hypoxia; toll-like receptor-9; triple-negative breast cancer