Abstract
Approximately 70% of patients with advanced breast cancer develop bone metastases, accompanied by complications, such as bone pain, fracture, and hypercalcemia. However, our understanding of the molecular mechanisms that govern this process remains fragmentary. Osterix (Osx) is a zinc finger-containing transcription factor essential for osteoblast differentiation and bone formation. Here, we identified the functional roles of Osx in facilitating breast cancer invasion and bone metastasis. Osx upregulation was associated with lymph node metastasis and was negatively prognostic for overall survival. Knockdown of Osx inhibited invasion of breast cancer and osteolytic metastasis by downregulating MMP9, MMP13, VEGF, IL-8, and PTHrP, which are involved in invasion, angiogenesis, and osteolysis; overexpression of Osx had the opposite effect. Moreover, MMP9 was a direct target of Osx and mediated the Osx-driven invasion of breast cancer cells. Together, our data showed that Osx facilitates bone metastasis of breast cancer by upregulating the expression of a cohort of genes that contribute to steps in the metastatic cascade. These findings suggest that Osx is an attractive target for the control of bone metastasis of breast cancers.
Highlights
Breast cancer, the second most commonly diagnosed cancer worldwide, affects ~12% of women and causes 14% of all cancer-related fatalities[1]
We found that high Osx expression was associated with lymph node metastasis and a poor prognosis for breast cancer
Knockdown of Osx inhibited the invasive capacity of breast cancer cells and osteolytic metastasis by downregulating MMP9, MMP13, vascular endothelial growth factor (VEGF), interleukin 8 (IL-8), and parathyroid hormone-related protein (PTHrP), whereas overexpression of Osx had the opposite effect
Summary
The second most commonly diagnosed cancer worldwide, affects ~12% of women and causes 14% of all cancer-related fatalities[1]. Cancer metastasis is a complex, multistage process that includes the steps of local invasion, intravasation, survival in the circulation, extravasation, and colonization[7] Involved in this process are various molecules, including: (1) metastasis initiation molecules, such as TWIST1, matrix metalloproteinases (MMPs), HIF1A, and vascular endothelial growth factor (VEGF)[8,9,10]; (2) metastasis progression molecules, such as PTGS2, EREG, LOX, ANGPLTL4, and CLDN211–14; and (3) metastasis virulence molecules, such as interleukin 8 (IL-8), vascular cell adhesion molecule 1 (VCAM-1), and parathyroid hormone-related protein (PTHrP)[15,16,17]. Despite progress with respect to the understanding of the molecular basis of bone metastasis in breast cancer, knowledge of the mechanisms underlying this process must be extended to identify targets for the prevention and treatment of bone metastases
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