Abstract B27: Osteoprotegerin's key role in inflammatory breast cancer: Bane or Boon.

Inflammatory breast cancer (IBC), the most aggressive form of breast cancer is presented with a rapidly enlarging erythematous breast, often with no discernible breast mass. IBC is lethal, highly metastatic and accounts for less than 5% of all diagnosed breast cancers; although in young African-American women recurrence rates are as high as 50%. Despite multimodality treatments such as systemic chemotherapy, adjuvant therapy, surgery and radiation, there is dismal prognosis with a 3-year survival rate of only about 40% compared to 85% among patients with non-IBC. Our long-term goal is to understand IBC biology, to evaluate its unique tumor microenvironment (TME), and to use that information to improve diagnosis, management, and survival rate in IBC patients. A proactive, complex and dynamic TME adds to the grim scenario of the disease by accumulating inflammatory and angiogenic growth factors and creating a niche for tumor cells. These cells rely on their TME which can drive a latent tumor to grow into different from the gross metastasis. Here, we performed thorough analysis and comparison of cytokine levels in the conditioned media obtained from inflammatory breast cancer (SUM149PT, SUM1315MO2; cells obtained from primary inflammatory ductal carcinoma of the breast) and normal cell lines (Primary human mammary epithelial cells; HMEC, 184B5; cells of normal mammary tissue obtained from a normal reduction mammoplasty). Inflammatory breast cancer cell lines secrete higher levels of cytokines such as osteoprotegerin (OPG), GRO, GRO-α, MIF, and MIP-1α. To fully comprehend the role of inflammatory cytokines in breast cancer tumorigenesis, we used “mammospheres” also known as tumorspheres or multicellular spheroids. Mammospheres represents an in vitro cultivation system which allows undifferentiated human mammary epithelial cells in suspension to propagate and form non-adherent colonies which recapitulate the in vivo spatial orientation. We compared the composition of conditioned media obtained from inflammatory breast cancer cell line and primary human mammary epithelial cell mammospheres. We observed striking differences in the level of osteoprotegerin (OPG) in the inflammatory breast cancer mammosphere conditioned medium as compared the one obtained from primary human mammary epithelial cells. We focused our study on OPG, a secreted member of the TNF superfamily that acts as a decoy receptor for the receptor activator of nuclear factor kappa B ligand (RANKL). Our work highlights the potential involvement of OPG in IBC tumor cell survival, metastases and reprogramming of mammosphere characteristics (size, number and, proliferation index) thus adding to the severity of disease. Collectively, our study significantly contributes to the understanding the role of OPG in cellular and molecular events involved in IBC progression and opens new avenues for strategic targeting of OPG and the development of novel therapeutic modalities for IBC. Citation Format: Sudeshna Goswami, Neelam Sharma-Walia. Osteoprotegerin9s key role in inflammatory breast cancer: Bane or boon. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B27.