Tuomela Johanna, Sandholm Jouko, Kauppila Joonas H, Lehenkari Petri, Harris Kevin W, Selander Katri S
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.
Oncol Lett. 2013 Dec;6(6):1665-1672. doi: 10.3892/ol.2013.1602. Epub 2013 Oct 4.
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 detected anti-invasive effects of chloroquine in these cell lines, the present study aimed to investigate the effects 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 expression . 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 favorable effects 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 levels . 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.
Toll样受体9（TLR9）是一种细胞内DNA受体，在乳腺癌和其他癌症中广泛表达。我们之前证明，诊断时肿瘤TLR9低表达与三阴性乳腺癌（TNBC）患者显著缩短的疾病特异性生存时间相关。对于这一乳腺癌预后最差的患者亚组，目前尚无靶向治疗方法。鉴于之前在这些细胞系中检测到氯喹的抗侵袭作用，本研究旨在探究氯喹对TLR9表达不同的两种TNBC临床亚型的影响。氯喹抑制基质金属蛋白酶（MMP）-2和MMP-9的mRNA表达及蛋白活性，而MMP-13的mRNA表达和蛋白水解活性则增加。尽管氯喹增强了TLR9的mRNA表达，但却抑制了TLR9蛋白表达。每天给小鼠腹腔注射（i.p.）氯喹（80毫克/千克/天），持续22天，并未抑制对照小干扰RNA（siRNA）或TLR9 siRNA的MDA-MB-231乳腺癌细胞的生长。总之，尽管氯喹对TNBC的侵袭和生存能力有有利影响，尤其是在缺氧条件下，但氯喹并不能阻止TLR9表达水平高或低的三阴性MDA-MB-231细胞的生长。这可能是由于氯喹对MMP-13表达的激活作用，或者是因为氯喹通过抑制TLR9表达，使得目前未知的分子途径被激活，从而使缺氧状态下TLR9表达低的TNBC细胞具有侵袭性。
