Abstract 3673: Role of IL-6 in inflammatory breast cancer and its modulation by Ganoderma lucid (Reishi)

Abstract

Inflammatory Breast Cancer (IBC) is an aggressive and lethal form of breast cancer with symptoms that include a diffuse redness and swelling of the breast. These signs resemble an inflammation, which may suggest the involvement of both immunological and inflammatory processes in the pathogenesis of this disease. Unique pathological findings indicate the presence of tumor emboli invading the dermal lymphatics of the breast; a process considered to be responsible for the inflammatory phenotype. However, these tumors produce inflammatory mediators such interleukin-6 (IL-6), which may act as a growth factor to contribute to cancer progression. Thus, cancer cells stimulated with or that secrete IL-6 via an autocrine loop, auto-activate these pathways resulting in malignant features such as enhanced invasion and increased metastasis. Our published data demonstrates that the medicinal mushroom, Ganoderma lucidum (Reishi), disintegrates tumor emboli, and reduces tumor growth. We hypothesize that IL-6 enhances while Reishi reduces IBC progression via modulation of the JAK-2/STAT-3 pathway both in vitro and in vivo. SUM-149 wound-healing assays were performed to determine the migratory phenotype of IBC cells stimulated with IL-6 or treated with Reishi. Immunoblots of SUM-149 and KPL-4 IBC cell lysates were performed to detect the expression of the JAK-2/STAT-3 signaling pathway and its downstream effectors upon Reishi treatment. Cell fractioning was performed to delineate if the proteins affected by Reishi belong to the nuclear or cytoplasmic fraction of the cell. For in vivo studies, severe combined immunodeficient (SCID) mice were injected with SUM-149 IBC cells in their mammary fat pad and treated via oral gavage with various concentrations of Reishi for 10wk. Our data from the in vitro studies indicate that IL-6 causes wound closure after 24h, an effect prevented by Reishi. Additionally, our data suggests that Reishi has an immunomodulatory role, demonstrated by its ability to reduce the phosphorylation of the IL-6/JAK-2/STAT-3 pathway. Cell fractioning of SUM-149 and KPL-4 cells show a drastic reduction in the expression of proteins corresponding to the nuclear fraction of the cell when treated Reishi. Finally, our in vivo data show a dose dependent reduction by 3.0 and 5.5 fold in tumor volume, when mice where treated with 7mg/kg BW and 14mg/kg BW of Reishi, respectively. This data suggests that Reishi may be used as a targeted therapeutic for women afflicted with IBC, for whom no direct therapeutics are currently available. We thank Dr. Kurebayashi (Kawasaki Medical School, Japan) for providing KPL-4 cells. This project was sponsored by Title V PPOHA US Department of Education #P031M105050 to UCC, NIH/RCMI #G12 MD007583 to UCC, NIH/INBRE #P20 GM103475 to UPR/UCC and a research donation from the Commonwealth of Puerto Rico to UCC's University Center of Integral and Complementary Medicine (CUMIC)/MMM. Citation Format: Yaliz Loperena-Alvarez, Luis A. Cubano, Michelle M. Martínez-Montemayor. Role of IL-6 in inflammatory breast cancer and its modulation by Ganoderma lucid (Reishi). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3673. doi:10.1158/1538-7445.AM2014-3673