cAMP-response-element-binding protein positively regulates breast cancer metastasis and subsequent bone destruction

Biochem Biophys Res Commun. 2010 Jul 23;398(2):309-14. doi: 10.1016/j.bbrc.2010.06.087. Epub 2010 Jun 25.

Abstract

cAMP-response-element-binding protein (CREB) signaling has been reported to be associated with cancer development and poor clinical outcome in various types of cancer. However, it remains to be elucidated whether CREB is involved in breast cancer development and osteotropism. Here, we found that metastatic MDA-MB-231 breast cancer cells exhibited higher CREB expression than did non-metastatic MCF-7 cells and that CREB expression was further increased by several soluble factors linked to cancer progression, such as IL-1, IGF-1, and TGF-beta. Using wild-type CREB and a dominant-negative form (K-CREB), we found that CREB signaling positively regulated the proliferation, migration, and invasion of MDA-MB-231 cells. In addition, K-CREB prevented MDA-MB-231 cell-induced osteolytic lesions in a mouse model of cancer metastasis. Furthermore, CREB signaling in cancer cells regulated the gene expression of PTHrP, MMPs, and OPG, which are closely involved in cancer metastasis and bone destruction. These results indicate that breast cancer cells acquire CREB overexpression during their development and that this CREB upregulation plays an important role in multiple steps of breast cancer bone metastasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Neoplasms / metabolism
  • Bone Neoplasms / secondary*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Cell Line, Tumor
  • Cyclic AMP Response Element-Binding Protein / genetics
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Insulin-Like Growth Factor I / pharmacology
  • Interleukin-17 / pharmacology
  • Matrix Metalloproteinases / genetics
  • Mice
  • Mice, Nude
  • Neoplasm Metastasis
  • Osteolysis / metabolism*
  • Osteolysis / pathology
  • Osteoprotegerin / genetics
  • Parathyroid Hormone-Related Protein / genetics
  • Transforming Growth Factor beta / pharmacology
  • Xenograft Model Antitumor Assays

Substances

  • Cyclic AMP Response Element-Binding Protein
  • Interleukin-17
  • Osteoprotegerin
  • Parathyroid Hormone-Related Protein
  • Transforming Growth Factor beta
  • Insulin-Like Growth Factor I
  • Matrix Metalloproteinases