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Tumor Commensal Microbiota Activates an S100A7-TLR4-STAT-3 Signaling to Induce Chronic Inflammation and Consequent Growth and Metastasis of Breast Cancer

Wilkie, Tasha, Wilkie

Abstract Details

2018, Doctor of Philosophy, Ohio State University, Molecular, Cellular and Developmental Biology.
With recent findings and a growing interest in the presence and role of bacterial microbiota in human breast tissue, it is important to elucidate the modulating role of these bacteria in breast cancer development, especially inflammation. Data show that cancerous breast tissue, like other common areas where cancer initiates, possess a unique commensal bacteria population. This breast tissue microbiota is mainly made up of gram negative which acts as a potential source of LPS in breast tissue. Endotoxins like LPS are well accepted initiators of the inflammatory environment in the pathology of diseases including breast cancer. This study provides significant progress in understanding the mechanism by which LPS induces the secretion of the pro-inflammatory protein S100A& which supports tumor growth and metastasis through modulation of TLR4-STAT3 signaling. Soluble S100A7 protein was found to increase the expression while acting as a ligand to TLR4, the putative receptor of LPS. Furthermore, S100A7 activates the MyD88 dependent TLR4 signaling to increase the expression of TNF-a, IL-6 and phosphorylation of STAT-3. High MyD88 expression was found to be associated with invasive breast carcinomas and in combination with S100A7 and TLR4 showed worse recurrence survival in patients with mutated p53 status. In addition, blockade of MyD88 dependent TLR4 signaling by a soluble inhibitor abrogated the S100A7 induced migration and invasion of BC cell lines. STAT3 signaling is known to promote initiation and progression of BC, and is activated by TLR4 mediated cytokines to maintain inflammatory responses. Inhibition of TLR4 signaling and S100A7reduces the activation of STAT3 signaling suggesting STAT3 is a downstream effector of the S100A7-axis in BC cell lines. In addition, in the presence of STAT3 inhibitors downregulation of S100A7 induced tumor volume and weight, lung metastasis and proliferative and angiogenic markers in mouse models. STAT3 was further shown to modulate S100A7 induced metastasis through its regulation of MMP9 expression and activity in tumors and recruited TAMs. Taken together these findings suggest that the commensal bacteria in cancerous breast tissue acts in the initiation and progression of breast cancer. Microbiota acting as an LPS source induce an S100A7-TLR4-STAT3 regulatory mechanism which controls the activity of mediators of BC growth and metastasis, specifically MMP9 in tumors and TAMs.
Ramesh Ganju (Advisor)
William Carson (Committee Member)
Xue-Feng Bai (Committee Member)
Kalpana Ghoshal (Committee Member)
Abhay Satoskar (Committee Member)
100 p.

Recommended Citations

Citations

  • Wilkie, Wilkie, T. (2018). Tumor Commensal Microbiota Activates an S100A7-TLR4-STAT-3 Signaling to Induce Chronic Inflammation and Consequent Growth and Metastasis of Breast Cancer [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1524214470077411

    APA Style (7th edition)

  • Wilkie, Wilkie, Tasha. Tumor Commensal Microbiota Activates an S100A7-TLR4-STAT-3 Signaling to Induce Chronic Inflammation and Consequent Growth and Metastasis of Breast Cancer. 2018. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1524214470077411.

    MLA Style (8th edition)

  • Wilkie, Wilkie, Tasha. "Tumor Commensal Microbiota Activates an S100A7-TLR4-STAT-3 Signaling to Induce Chronic Inflammation and Consequent Growth and Metastasis of Breast Cancer." Doctoral dissertation, Ohio State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=osu1524214470077411

    Chicago Manual of Style (17th edition)