SREBP-2 aggravates breast cancer associated osteolysis by promoting osteoclastogenesis and breast cancer metastasis.

Bone is one of the most common sites of breast cancer metastasis and a major cause of high mortality in these patients. Thus, further understanding the molecular mechanisms regulating breast cancer-induced osteolysis is critical for the development of more effective treatments. In this study, we demonstrated that important roles sterol regulatory element-binding protein 2 (SREBP-2) play in osteoclast formation a function, and in breast cancer metastasis. SREBP-2 expression was found to be induced during the early stages of osteoclast formation under the control of the RANKL/cAMP-response element binding protein (CREB) signaling cascade. SREBP-2 is subsequently translocated into the nucleus where it participates with other transcriptional factors to induce the expression of NFATc1 required for mature osteoclast formation. Additionally, SREBP-2 was also found to be highly expressed in breast cancer tissues and correlated with a poor prognosis. SREBP-2 was similarly under the transcriptional control of CREB and its induction regulates the expression of matrix metalloproteinases (MMPs), key degradative enzymes involved in bone metastases by breast cancer cells. Accordingly, targeting of SREBP-2 with Fatostatin which specifically inhibits SCAP (SREBP cleavage-activating protein) and prevents SREBP activation, attenuated breast cancer-induced osteolysis in vivo. Collectively, our results suggest that SREBP-2 plays a critical role in regulating osteoclastogenesis and contributes to breast cancer-induced osteolysis. Thus, SREBP-2 inhibition is a potential therapeutic approach for breast cancer patients with osteolytic bone lesions.