Inflammatory breast cancer (IBC) is an angioinvasive form of breast cancer associated with a high incidence of early nodal and systemic metastasis. In contrast to the recent decrease in breast cancer incidence in the United States, the annual incidence of IBC continues to increase with a concomitant increase in mortality. The hallmark symptoms of IBC are redness, swelling, skin thickening and an orange peel pitted texture of the skin which are caused by the buildup of fluid (lymph) in the skin of the breast. This fluid buildup occurs because cancer cells have blocked lymph vessels in the skin, preventing the normal flow of lymph through the tissue. In addition to the cancer stem cells and the intrinsic signals regulating them, the tumor microenvironment (TME) also plays a major role. Inflammatory TME has been described as a major axis of evil in IBC, therefore its thorough understanding will be critical in finding possible underlying mechanisms, their potential crosstalk with oncogenic signaling pathways, and more importantly finding new targets to control IBC. Our long term goal is to understand IBC biology, to evaluate its unique TME, and to use that information to improve diagnosis, management, and survival rate in IBC patients. These cells rely on their TME which can drive a latent tumor to grow into a highly metastatic tumor. Inflammatory TME can suppress antitumor immunity, aggravate pro-inflammatory pro-tumorigenic factors and eventually overcome the beneficial effects of the anti-cancer drugs. When we compared the secretions from the cell lines of the IBC cell lines (SUM149PT; SUM1315MO2) with those obtained from the primary human mammary epithelial cells (HMEC), the secretions were found to be enriched with Osteoprotegerin (OPG), GRO, GRO-α, MIF, MIP-1α. To gain a complete understanding of the role of one of the most abundant secreted protein OPG in IBC tumorigenesis, we used, in vitro cultivation system called ‘mammospheres’, which contain progenitor cells able to clonally reproduce functional complex structures in vitro resembling the in vivo mammary tree is generated. Therefore, we aim to evaluate the role of OPG on ‘mammosphere’ characteristics (size, viable cells in the spheres) which will be a valuable strategy to find new targets for IBC treatment. Our work highlights the potential autocrine and paracrine effects of OPG in IBC tumor cell survival, angiogenesis, cancer stem cell population, mammosphere branching and metastases adding to the severity of disease. Along with high levels of OPG, we also observed high levels of PGE2 which has pleiotrophic effects on cell proliferation, motility, invasion and angiogenesis. PGE2 and OPG together modulate the tumor microenvironment axis of the IBC - making it highly metastatic and invasive and thus contributing to the severity of the disease.

Citation Format: Sudeshna Goswami, Neelam Sharma-Walia. Tumor microenvironment of inflammatory breast cancer is critical for mammosphere branching and proliferation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2610. doi:10.1158/1538-7445.AM2013-2610