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Immune Receptor Signalling in Breast Cancer Progression
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Breast Cancer is the second most common diagnosed malignancy in India. Approximately per year 50,000-70,000 women are dying because of breast cancer. In the late stage of cancer, metastasis is the key process which is responsible for the death. Epithelial to mesenchymal transition is the hallmark for tumor development. Different molecules like different proteases and their abnormal synthesis catalyze the epithelial to mesenchymal transition and metastasis. Thus, blocking of those molecules is one of the areas for drug development.
At present different innate immune molecules and their ligands are in clinical trial for cancer therapy. But, the result of those clinical trials is not unidirectional. Thus, underlying molecular mechanism of those innate adjuvant ligands for breast cancer suppression (progression?) not yet fully understood.
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Within the tumor microenvironment, antigen presenting cells shows high expression of immune receptor thus, may not able to produce inflammatory cytokine and favoring the immune tolerance and reduce TLR activation. Thus TLR may be activated both in cancer associated fibroblast (CAF) and tumor associated macrophages (TAM) and tumor cells. Activated TLR in TAM may induces the release of IFNγ and in tumor cell induces the proinflammatory cytokine secretion and help in the proliferation and activation leading towards EMT.
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Important findings:
(1) Our group has showed - Toll like Receptor -3 (TLR3) also present in cancer cell membrane and induce cellular proliferation through MyD88 - NF-κB - Cylin D1 pathway, which is interdependent of endosomal localization and TRIF signalling pathway [Front Oncol. 2020; 10: 1780.] .
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Fig: Mechanism of MyD88 adopter-mediated surface TLR3 signaling. TLR3 ligand polyinosinic:polycytidylic acid [poly(I:C)] induces the recruitment of the MyD88 complex and activation of downstream signaling cascade. Downstream activation of IRAK-1, TAK1, TRAF6, and TAB1 enables translocation of NF-κB, p65 to the nucleus to induce the secretion of proinflammatory cytokine IL-6 that induces cell proliferation via cyclin D1 [ Ref: Singh A , Devkar R and Anupam Basu. Front Oncol. 2020; 10: 1780],
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(ii) We have shown the at blocking of proteases like Urokinase Plasminogen Activator and Matrix metalloproteinase-9 in Breast cancer cells like MMDA MB 231, can reduce EMT and cellular migration or metastasis through increase in the expression of E- Cadherin (Moirangthem et al. Sci. Rep. 6, 21903; (2016). Our group also reported that cell membrane localization and dual role of innate receptor TLR-3 in breast cancer (Bondhpadhyay et. al. Tumor Biology, 2015)
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Fig: Model of control of breast cancer progression by blocking uPA and MMP9 (Ref. Moirangthem et al. and Anupam Basu, : ‘Sci. Rep. 6, 21903; (2016).
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