Abstract 1112: Role of osteoprotegerin in inflammatory and invasive breast cancer

Abstract Inflammatory breast cancer (IBC) is a highly aggressive and angioinvasive form of breast cancer associated with a high incidence of early nodal and systemic metastasis. A proactive, complex and dynamic tumor microenvironment of IBC adds to the grim scenario of the disease by accumulating inflammatory and angiogenic growth factors and creating a niche for the growth and metastasis of tumor cells. The secretions from the primary inflammatory ductal carcinoma of the breast (SUM149PT), and highly invasive ductal carcinoma cells (SUM1315MO2) secrete unusually high levels of osteoprotegerin (OPG) as compared to those obtained from the primary human mammary epithelial cells (HMEC). OPG, which plays a pivotal role in bone remodeling by regulating osteoclast formation, is a multifaceted molecule, and has been found to be involved in multiple myeloma and prostate cancers. This prompted us to examine the role of OPG in the aggressive breast cancers, which has not been deciphered till date. For a better understanding of the OPG functions, apart from using adherent cells, we used in vitro ‘sphere culture’ as our working model. We studied the functional significance of OPG in aggressive breast cancer biology by utilizing well standardized techniques such as OPG staining (immunohistochemistry, immunofluorescence), OPG secretion (ELISA), angiogenesis (in vitro tube formation), proliferation (MTT), and cell cycle/aneuploidy analysis (PI staining). We demonstrated that (1) OPG secretion as well as protein level is upregulated in IBC (SUM149PT) and highly Invasive ductal carcinoma cells (SUM1315MO2), and their spheres compared to those of normal human mammary epithelial (HMEC); (2) OPG stained specifically in patient breast cancer tissue samples when compared to the uninvolved tissue from the same patient; (3) OPG rich secretions from IBC and highly invasive breast cancer were highly angiogenic; (4) OPG enriched culture medium induced proliferation of the control HMEC spheres; (5) the presence of OPG triggered the onset of aneuploidy in the control HMEC adherent cells as well as spheres. The functional studies showing the biological significance of OPG (i,e its effect on proliferation, angiogenesis, and aneuploidy) were confirmed using recombinant human OPG and OPG rich/depleted medium obtained from breast cancer cells. Overall our studies highlight the link between OPG and aneuploidy in aggressive breast cancer cells, and opens up avenues for new therapeutic targets for treating IBC. Citation Format: Sudeshna Goswami, NEELAM SHARMA-WALIA. Role of osteoprotegerin in inflammatory and invasive breast cancer. [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 1112. doi:10.1158/1538-7445.AM2014-1112