Abstract P4-04-07: Breast cancer tissue context determines whether inflammation with bacterial/psoriasin signature is pro- or anti-carcinogenesis

Abstract

Abstract Objective: It is often neglected that breast tissue microbiota and systematic bacterial infection actively and potently influence the development of breast cancer. With reports of both pro-cancer and anti-cancer roles of bacterial inflammation, the actual effect of bacterial inflammation to breast cancer and its mechanism remain unclear and are of our interests. Rationale: Different from other human tissues, breast tissue microbiota is majorly Gram-negative at both normal and pathological statuses. We discovered that bacterial inflammation in breast tissue has a signature of Psoriasin (S100A7) impact which resembles psoriasis of the skin. However, this Psoriasin mediated inflammation can either promote or inhibit breast cancer development. We hypothesize that different tissue context determines the differential effects of bacterial/Psoriasin inflammation on breast cancer development. Results: We first verified the presence of commensal Gram-negative microbiota (and LPS) in breast tissues under normal and pathological circumstances using mouse models. We observed that in both normal and cancerous breast tissues, bacterial factors (such as LPS) found in breast triggered secretion of Psoriasin by mammary adenocytes and Psoriasin mediated inflammation. This type of inflammation is featured by macrophage recruitment and ductal infiltration induced by Psoriasin. However, in normal tissues, macrophages matured into M1 type (iNOS positive); whereas in cancerous tissues, macrophages matured into M2 type (Arginase-1 positive). In normal tissues, Psoriasin and M1 caused an unresolved accumulation of inflammation in mammary ducts without lactation, which might lead to accelerated cancer initiation. In tumors, Psoriasin and M2 increased tumor growth and metastasis in immune-competent mammary epithelial specific expression mouse models. This was further confirmed in human patient samples and large cohort bioinformatic analysis. Using human breast cancer cell lines and nude mice, we elucidated that inflammation related Psoriasin upregulation and secretion in cancer cells had differential effects on tumor growth depending on its tissue source. Psoriasin increased cell proliferation and tumor growth in basal-like cancer cells; whereas it decreased cell proliferation and tumor growth in non-basal-like cancer cells. And this difference was mediated through differential regulation of the NF-κB/miR-29b/p53 pathway. in vitro molecular study and in vivo models verified the important role of miR-29b switch in the differential effects of Psoriasin in different tissue types of breast cancer cells. Conclusion: Bacterial/Psoriasin inflammation differentially influences breast cancer development depending on the tissue context, and it involves the effects on macrophages and cancer cells. Our work provides novel potentials to improving prognosis and targeting inflammation to treat breast cancer in personalized medicine. Citation Format: Helong Zhao, Mohd W Nasser, Tasha Wilkie, Ramesh K Ganju. Breast cancer tissue context determines whether inflammation with bacterial/psoriasin signature is pro- or anti-carcinogenesis [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-04-07.