Abstract
Bone metastases occur in most advanced breast cancer patients and cause serious skeletal-related complications. The mechanisms by which bone metastasis seeds develop in primary tumors and specifically colonize the bone remain to be elucidated. Here, we show that forkhead box F2 (FOXF2) functions as a master transcription factor for reprogramming cancer cells into an osteomimetic phenotype by pleiotropic transactivation of the BMP4/SMAD1 signaling pathway and bone-related genes that are expressed at early stages of bone differentiation. The epithelial-to-osteomimicry transition regulated by FOXF2 confers a tendency on cancer cells to metastasize to bone which leads to osteolytic bone lesions. The BMP antagonist Noggin significantly inhibits FOXF2-driven osteolytic bone metastasis of breast cancer cells. Thus, targeting the FOXF2-BMP/SMAD axis might be a promising therapeutic strategy to manage bone metastasis. The role of FOXF2 in transactivating bone-related genes implies a biological function of FOXF2 in regulating bone development and remodeling.
Highlights
Bone metastases occur in most advanced breast cancer patients and cause serious skeletalrelated complications
We provide clinical and experimental evidence to illustrate the role of forkhead box F2 (FOXF2) in breast cancer bone metastasis and uncover mechanisms underlying the osteomimetic formation and osteolytic bone metastasis of breast cancer cells, in which FOXF2 programs epithelium-to-osteomimicry transition (EOT) by pleiotropic transactivation of the BMP4/SMAD1 signaling pathway and bone-related genes that are expressed at early stages of bone differentiation
We analyzed the relationship between FOXF2 expression and distant metastasis-free survival (DMFS) or non-bone/other organ metastasis-free survival (NBMFS) in overall cases and in different subtype cases based on our reverse transcription–quantitative polymerase chain reaction (RT-Quantitative PCR (qPCR)) data of primary breast cancer tissues
Summary
Bone metastases occur in most advanced breast cancer patients and cause serious skeletalrelated complications. We show that forkhead box F2 (FOXF2) functions as a master transcription factor for reprogramming cancer cells into an osteomimetic phenotype by pleiotropic transactivation of the BMP4/ SMAD1 signaling pathway and bone-related genes that are expressed at early stages of bone differentiation. We provide clinical and experimental evidence to illustrate the role of FOXF2 in breast cancer bone metastasis and uncover mechanisms underlying the osteomimetic formation and osteolytic bone metastasis of breast cancer cells, in which FOXF2 programs epithelium-to-osteomimicry transition (EOT) by pleiotropic transactivation of the BMP4/SMAD1 signaling pathway and bone-related genes that are expressed at early stages of bone differentiation. Our findings suggest that targeting the FOXF2-BMP/SMAD axis might be a promising therapeutic strategy to manage breast cancer bone metastasis
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