Mourskaia A A, Dong Z, Ng S, Banville M, Zwaagstra J C, O'Connor-McCourt M D, Siegel P M
Department of Medicine, McGill University, Montreal, Quebec, Canada.
Oncogene. 2009 Feb 19;28(7):1005-15. doi: 10.1038/onc.2008.454. Epub 2008 Dec 15.
Transforming growth factor (TGF)-beta signaling is a potent modulator of the invasive and metastatic behavior of breast cancer cells. Indeed, breast tumor responsiveness to TGF-beta is important for the development of osteolytic bone metastases. However, the specific TGF-beta isoforms that promote breast cancer outgrowth in bone is unknown. We demonstrate that expression of a TGF-beta ligand trap, which neutralizes TGF-beta1 and TGF-beta3, in MDA-MB-231 breast cancer cells diminished their outgrowth in bone and reduced the severity of osteolytic lesion formation when compared with controls. We further show that a reduction or loss of TGF-beta1 expression within the bone microenvironment of TGF-beta1+/- and TGF-beta1-/- mice significantly reduced the incidence of breast tumor outgrowth compared with wild-type animals. Interestingly, those tumors capable of growing within the tibiae of TGF-beta1-deficient mice had upregulated expression of all three TGF-beta isoforms. Finally, breast cancer cells expressing the TGF-beta ligand trap showed a pronounced reduction in their ability to form osteolytic lesions when injected into the tibiae of TGF-beta1+/- mice. Thus, our studies show that both host- and tumor-derived TGF-beta expression plays a critical role during the establishment and outgrowth of breast cancer cells in bone.
转化生长因子（TGF）-β信号通路是乳腺癌细胞侵袭和转移行为的有力调节因子。事实上，乳腺肿瘤对TGF-β的反应性对于溶骨性骨转移的发展很重要。然而，促进乳腺癌在骨中生长的特定TGF-β亚型尚不清楚。我们证明，在MDA-MB-231乳腺癌细胞中表达可中和TGF-β1和TGF-β3的TGF-β配体陷阱，与对照相比，可减少其在骨中的生长并降低溶骨性病变形成的严重程度。我们进一步表明，与野生型动物相比，TGF-β1+/-和TGF-β1-/-小鼠骨微环境中TGF-β1表达的减少或缺失显著降低了乳腺肿瘤生长的发生率。有趣的是，那些能够在TGF-β1缺陷小鼠的胫骨内生长的肿瘤，其所有三种TGF-β亚型的表达均上调。最后，表达TGF-β配体陷阱的乳腺癌细胞注射到TGF-β1+/-小鼠的胫骨中时，其形成溶骨性病变的能力明显降低。因此,我们的研究表明，宿主来源和肿瘤来源的TGF-β表达在乳腺癌细胞在骨中的定植和生长过程中都起着关键作用。
