Dynamic interactions between cancer cells, supportive stromal cells, the extracellular matrix (ECM), and the immune system are critical to breast cancer progression. Periostin is an ECM protein correlated to poor outcomes in breast cancer. Periostin is structurally similar to another ECM protein TGFBI that plays an opposite role in cancer. The first portion of this thesis focused of periostin in breast cancer progression. First, the periostin/TGFBI ratio was associated with increased breast tumor size and progression in mice and humans. In vitro, breast cancer cells secreted periostin, which led to expression and activation of the cytokine TGF-β in a positive regulatory loop. In a mouse mammary cancer model, treatment with the angiotensin receptor blocker losartan, an upstream inhibitor of TGF-β production, decreased the periostin/TGFBI ratio and led to decreased cancer progression. Further in vitro, periostin decreased VEGF secretion, increased TGF- β secretion, inhibited adhesion, and decreased nonspecific phagocytosis of macrophages. In vivo, periostin pre-treated RAW macrophages co-injected with 4T1 cancer cells led to decreased tumor size compared to un-treated macrophages plus cancer cells. Together, the experimental observations indicated that the periostin/TGFBI expression ratio, which can be altered by losartan is associated with breast cancer progression, and, that periostin may also have paradoxical effects on macrophages. The second of portion of this thesis highlights multiple aspects of the management of orthopedic patients.
