Immune adaptor
protein like
STING/MITA regulate innate immune response and plays a critical role in
inflammation in the tumor microenvironment and regulation of
metastasis including
breast cancer.
Chromosomal instability in highly metastatic cells releases fragmented chromosomal parts in the cytoplasm, hence the activation of
STING via an increased level of cyclic dinucleotides (cDNs) synthesized by cGMP-
AMP synthase (cGAS). Cyclic dinucleotides 2' 3'-cGAMP and it's analog can potentially activate
STING mediated pathways leading to nuclear translocation of p65 and IRF-3 and transcription of inflammatory genes. The differential modulation of
STING pathway via 2' 3'-cGAMP and its analog and its implication in breast
tumorigenesis is still not well explored. In the current study, we demonstrated that
c-di-AMP can activate type-1 IFN response in ER negative breast
cancer cell lines which correlate with
STING expression.
c-di-AMP binds to
STING and activates downstream IFN pathways in
STING positive metastatic MDA-MB-231/MX-1 cells. Prolonged treatment of
c-di-AMP induces cell death in
STING positive metastatic MDA-MB-231/MX-1 cells mediated by IRF-3.
c-di-AMP induces IRF-3 translocation to mitochondria and initiates
Caspase-9 mediated cell death and inhibits clonogenicity of
triple-negative breast cancer cells. This study suggests that
c-di-AMP can activate and modulates
STING pathway to induce mitochondrial mediated apoptosis in
estrogen-receptor negative
breast cancer cells.