Chloroquine has tumor-inhibitory and tumor-promoting effects in triple-negative breast cancer

Area of Science:

• Oncology
• Immunology
• Pharmacology

Background:

• Toll-like receptor-9 (TLR9) is an intracellular DNA receptor implicated in various cancers, including triple-negative breast cancer (TNBC).
• Low tumor TLR9 expression correlates with poorer survival in TNBC patients, a subgroup lacking targeted therapies.
• Chloroquine has demonstrated in vitro anti-invasive properties in TNBC cell lines.

Purpose of the Study:

• To investigate the in vivo effects of chloroquine on two clinical subtypes of TNBC with differing TLR9 expression levels.
• To evaluate chloroquine's impact on tumor growth and molecular markers associated with invasion and TLR9 expression.

Main Methods:

• In vitro assessment of chloroquine's effects on matrix metalloproteinase (MMP) and TLR9 expression and activity.
• In vivo study involving daily intraperitoneal administration of chloroquine to mice bearing MDA-MB-231 TNBC cells (control siRNA or TLR9 siRNA).
• Monitoring of tumor growth inhibition over 22 days.

Main Results:

• In vitro, chloroquine suppressed MMP-2 and MMP-9 but increased MMP-13 expression and activity.
• Chloroquine enhanced TLR9 mRNA but suppressed TLR9 protein expression in vitro.
• Daily chloroquine treatment in vivo did not inhibit the growth of MDA-MB-231 cells, regardless of TLR9 expression levels.

Conclusions:

• Despite promising in vitro anti-invasive effects, chloroquine failed to inhibit TNBC cell growth in vivo.
• Potential mechanisms for this lack of efficacy include chloroquine-induced MMP-13 activation or suppression of TLR9, potentially enabling aggressive TNBC behavior.
• Further research is needed to understand the complex interplay of chloroquine, TLR9, MMPs, and TNBC aggressiveness, especially under hypoxic conditions.