In cancer progression, proteolytic enzymes like serine proteases and metalloproteinases degrade the basement membrane enabling the tumor cells to invade the adjacent tissues. Thus, invasion and metastasis are augmented by these enzymes. Simultaneous silencing of uPA and MMP9 in breast cancer cells decreased the wound healing, migratory, invasive and adhesive capacity of the cells. After simultaneous down regulation, cells were seen to be arrested in the cell cycle. There was a remarkable increase in the expression of cell to cell adhesion molecule E–cadherin, and decrease in Vimentin and Snail expression. In addition, there was a significant decrease in the expression of the stem cell marker Oct-4. In the breast tumor samples it has been observed that, tumors, expressing higher level of uPA and MMP9, express less amount of E–cadherin. It has also been observed that few tumors also show, Vimentin positive in the ductal epithelial area. Thus, our model can help for checking the aggressive tumor invasion by blocking of uPA and MMP9. Our present observations also give the concept of the presence of aggressive epithelial cells with mesenchymal nature in the tumor micro-environment, altering the expression of EMT genes.

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Toll like receptors are expressed by variety of cells, mainly immune cells and also found to have role in the tumor microenvironment. Among them, Toll like receptors-4 is found to modulate tumor progression. But definitive action of TLR4 in tumor progression is not well understood. In the present study, in breast tumor samples, expression of TLR4 was studied by immunohistochemistry method while MMP2 and MMP9 expression were studied by gelatin zymography. Kaplan Meier plotter was used to test survivability. Breast cancer cells -MCF7, MDA MB 231, T47D were studied in the presence of TLR4 lignd LPS, with the help of MTT assay, BrdU incorporation assay, scratch wound healing assay and invasion assay. Activation of TLR4 in MCF7 which is TP53 wild type has no significant effect in proliferative rate, adhesiveness and invasiveness. While in MDA-MB-231 and T47D which are TP53 mutant, there were a significant increase in adhesiveness and migratory ability, observed., TLR4 had been expressed in breast tumor of invasive ductal carcinoma (IDC) and was found to be significantly correlated with lymph node involvement. Kaplan Meier plotter analysis revealed that high TLR4 expression might serve as an immune-protectant in invading cancer cells of TP53 wild state. It has been revealed that activation of TLR4 in breast cancer cells leads to higher expression of EMT related genes along with matrix metalloproteinases helping in migration and invasion of cells. Kaplan Meier plotter analysis revealed that TP53 wild status of the patient along with high TLR4 expression has a good overall survival of the patients.

Purpose: TLR9 is the sensor of fragmented nucleic acid signature as a part of innate immune surveillance. TLR9 can recognize the DNA fragments released from the chemotherapy-treated cancer cells in tumour tissue and induce an inflammatory response. The aim of this was toinvestigate the prognostic importance and survivability benefit of TLR9 expression in breast cancer patients treated with neoadjuvant chemotherapy. Methods: Expression of TLR9 in breast carcinoma samples was studied in two patient cohorts, with neoadjuvant chemotherapy (NACT), and without NACT, by immunohistochemistry. Expression of TLR9 was analysed in relation to prognosis, overall survivability as well as risk factor analysis for neoadjuvant chemotherapy treatment using web-tools like SurvExpress and K-M Plotter. Results: TLR9 was expressed in malignant epithelial cancer cells as well as in adjacent stromal cells. TLR9 in malignant epithelial cells was significantly high in patients treated with neoadjuvant chemotherapy compared to the patients without neoadjuvant chemotherapy. The prognostic and survival analysis by SurvExpress and Kaplan-Meier plotter demonstrated that high TLR9 expression is related to better overall survival in patients treated with NACT. Conclusions: Thus, we are showing for the first time that TLR9 is good prognostic marker in breast cancer treated with neoadjuvant chemotherapy and can be used for the selection of the neo-adjuvant regime