Low TLR9 expression defines an aggressive subtype of triple-negative breast cancer

Abstract

Toll-like receptor-9 (TLR9) is a DNA receptor widely expressed in cancers. Although synthetic TLR9 ligands induce cancer cell invasion in vitro, the role of TLR9 in cancer pathophysiology is unclear. We discovered that low tumor TLR9 expression is associated with significantly shortened disease-specific survival in patients with triple negative but not with ER+ breast cancers. A likely mechanism of this clinical finding involves differential responses to hypoxia. Our pre-clinical studies indicate that while TLR9 expression is hypoxia-regulated, low TLR9 expression has different effects on triple negative and ER+ breast cancer invasion in hypoxia. Hypoxia-induced invasion is augmented by TLR9 siRNA in triple negative, but not in ER+ breast cancer cells. This is possibly due to differential TLR9-regulated TIMP-3 expression, which remains detectable in ER+ cells but disappears from triple-negative TLR9 siRNA cells in hypoxia. Our results demonstrate a novel role for this innate immunity receptor in cancer biology and suggest that TLR9 expression may be a novel marker for triple-negative breast cancer patients who are at a high risk of relapse. Furthermore, these results suggest that interventions or events, which induce hypoxia or down-regulate TLR9 expression in triple-negative breast cancer cells may actually induce their spread.

Biopathological Significance of TLR9 Expression in Cancer Cells and Tumor Microenvironment Across Invasive Breast Carcinomas Subtypes

“…TLR9 overexpression by cancer epithelial [35][36][37][38][39][40][41]. Results from our study are in agreement with those reported in the literature [42].…”

Tumor infiltrating CD8+T lymphocyte count is independent of tumor TLR9 status in treatment naïve triple negative breast cancer and renal cell carcinoma

“…4,6 Although initially thought to be limited only to the innate immune system, it is now well established that TLR9 is widely expressed also in various cancer types, such as in breast, brain, gastric, lung, ovarian, prostate and kidney cancers as well as in cancers of the GI tract. [7][8][9][10][11][12][13][14][15][16][17] Stimulation of TLR9 expressing cancer cells with bacterial DNA-like, synthetic TLR9 ligands induces MMP-13-mediated invasion in vitro. 7,10,18,19 Based on these findings, it was expected that tumor TLR9 mediates invasion and metastasis and that high tumor TLR9 expression would be associated with worse survival.…”

“…In these cancers, low tumor TLR9 expression has been shown to predict poor prognosis and short disease-specific survival. 11,13 Among breast cancer patients, those with TNBC are considered to have the worst prognosis. 21,22 This is because of the generally aggressive behavior of such tumors and also because these tumors lack the expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2), which would allow targeted treatment.…”

Investigação do papel de SIGIRR/IL-1R8 no <i>crosstalk</i> entre células tumorais e o infiltrado leucocitário

“…In addition, it has been previously described that silencing of TLR4 and TLR9 in tumors are associated with mammary tumor progression and decreased activation of IFN-γ-dependent antitumor T-cell responses (49)(50)(51). In this context, our findings reveal an important tumor-promoting function for IL-1R8, a critical break for TLR and ILR stimulus, in breast tumors by supporting cancer associated inflammation and impairing anti-tumor immunity.…”