Abstract
Aggressive breast cancer is associated with poor patient outcome and characterized by the development of tumor cell variants that are able to escape from control of the immune system or are resistant to targeted therapies. The complex molecular mechanisms leading to immune escape and therapy resistance are incompletely understood. We have previously shown that high miR-519a-3p levels are associated with poor survival in breast cancer. Here, we demonstrate that miR-519a-3p confers resistance to apoptosis induced by TRAIL, FasL and granzyme B/perforin by interfering with apoptosis signaling in breast cancer cells. MiR-519a-3p diminished the expression of its direct target genes for TRAIL-R2 (TNFRSF10B) and for caspase-8 (CASP8) and its indirect target gene for caspase-7 (CASP7), resulting in reduced sensitivity and tumor cell apoptosis in response to apoptotic stimuli. Furthermore, miR-519a-3p impaired tumor cell killing by natural killer (NK) cells via downregulation of the NKG2D ligands ULBP2 and MICA on the surface of tumor cells that are crucial for the recognition of these tumor cells by NK cells. We determined that miR-519a-3p was overexpressed in more aggressive mutant TP53 breast cancer that was associated with poor survival. Furthermore, low levels of TRAIL-R2, caspase-7 and caspase-8 correlated with poor survival, suggesting that the inhibitory effect of miR-519a-3p on TRAIL-R2 and caspases may have direct clinical relevance in lowering patient’s prognosis. In conclusion, we demonstrate that miR-519a-3p is a critical factor in mediating resistance toward cancer cell apoptosis and impairing tumor cell recognition by NK cells. This joint regulation of apoptosis and immune cell recognition through miR-519a-3p supports the hypothesis that miRNAs are key regulators of cancer cell fate, facilitating cancer progression and evasion from immunosurveillance at multiple and interconnected levels.
Highlights
Breast cancer is the most common type of cancer in women worldwide and represents the second leading cause of cancer mortality in women.[1,2] The broad molecular and pathological heterogeneity of breast cancer subtypes is reflected by the diversity of the underlying biology and a poor prognosis of some subtypes.[3,4] Targeted therapies have fundamentally improved patient outcome for estrogen receptor-positive luminal A as well as for HER2-positive breast cancer subtypes.[5]
We investigated the effects of miR-519a-3p on the susceptibility of breast cancer cells toward natural killer (NK) cell-mediated cytotoxicity as a potential mechanism for tumor cell escape from immune cell recognition and a rather physiological trigger for apoptosis
We show that miR-519a-3p leads to inhibition of TRAILand Fas ligand (FasL-)induced apoptosis in breast cancer cell lines by directly targeting the proapoptotic TNFRSF10B (TRAIL-R2) and CASP8 messenger RNAs (mRNAs)
Summary
Breast cancer is the most common type of cancer in women worldwide and represents the second leading cause of cancer mortality in women.[1,2] The broad molecular and pathological heterogeneity of breast cancer subtypes is reflected by the diversity of the underlying biology and a poor prognosis of some subtypes.[3,4] Targeted therapies have fundamentally improved patient outcome for estrogen receptor-positive luminal A as well as for HER2-positive breast cancer subtypes.[5]. TRAIL efficiently induced apoptosis in several cell line models;[15] it has been reported to even increase cell growth and metastasis formation in TRAIL-resistant tumors.[16,17] In addition to targeting the cancer cells directly, the (re-)activation of the immune system has become a promising strategy in current clinical trials for the treatment of solid tumors, including breast cancer.[18,19] Activated immune cells, like T and natural killer (NK) cells, can eliminate tumor cells by inducing apoptosis This is mediated via exocytosis of cytotoxic granules from NK cells, containing perforin and granzymes, as well as via induction of the TNF superfamily (Fas ligand and TRAIL) signaling pathways in the tumor cells.[20] some tumors escape T-cell as well as NK-cell recognition and/or their killing machinery using mechanisms that are incompletely understood.[21,22].
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