cAMP-response-element-binding protein positively regulates breast cancer metastasis and subsequent bone destruction.
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.
Son
Jieun
J
Department of Cell and Developmental Biology, Dental Research Institute, School of Dentistry, Seoul National University, Seoul 110-749, Republic of Korea.
Lee
Jong-Ho
JH
Kim
Ha-Neui
HN
Ha
Hyunil
H
Lee
Zang Hee
ZH
D000818:Animals; D001859:Bone Neoplasms / Q000378:metabolism / Q000556:secondary*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D020381:Interleukin-17 / Q000494:pharmacology; D020782:Matrix Metalloproteinases / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D010014:Osteolysis / Q000378:metabolism* / Q000473:pathology; D053244:Osteoprotegerin / Q000235:genetics; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D017362:Cyclic AMP Response Element-Binding Protein; D020381:Interleukin-17; D053244:Osteoprotegerin; D044162:Parathyroid Hormone-Related Protein; D016212:Transforming Growth Factor beta; D007334:Insulin-Like Growth Factor I; D020782:Matrix Metalloproteinases