Preclinical and clinical studies of novel breast cancer drugs targeting molecules involved in protein kinase C signaling, the putative metastasis-suppressor gene Cap43 and the Y-box binding protein-1.
Breast cancer is a common cause of tumors in women. The development of effective adjuvant therapies using drugs such as anthracyclines, taxanes, and aromatase inhibitors has improved the survival of breast cancer patients. Molecular cancer therapeutics are also attracting attention, and targeted molecular therapies, such as trastuzumab, have already contributed to effective new treatments for breast cancer. Other candidate targeted molecular therapies for breast cancer, including erlotinib, gefitinib, lapatinib, bevacizumab, and celecoxib, are currently undergoing clinical evaluation, and promising results are expected. The current review provides an up-to-date summary of the preclinical and clinical development of these drugs for breast cancer. In particular, we focus on therapies targeting protein kinase C (PKC) signaling, the putative metastasis-suppressor gene Cap43/N-myc downstream-regulated gene 1 (NDRG1)/differentiation-related gene-1 (Drg-1), and the Y-box binding protein-1 (YB-1). The PKC signaling pathway is widely considered to be a promising target for the development of novel therapeutics. Cap43 expression is significantly modulated by estrogen and/or anti-estrogens in breast cancer cells that are positive for estrogen receptor-alpha (ER-alpha). Cap43 is therefore of particular interest as a molecular indicator of the therapeutic efficacy of anti-estrogenic agents in breast cancer. The nuclear expression of YB-1 plays an essential role in the acquisition of malignant characteristics by breast cancer cells, through epidermal growth factor receptor 2 (HER2)-Akt-dependent pathways. Basic research investigating the key selective molecular changes that sustain breast cancer growth and progression, as demonstrated for PKC, Cap43, and YB-1, is allowing the development of specific targeted molecular diagnostics and therapeutics.
Fujii
Teruhiko
T
National Hospital Organization Kyushu Medical Cancer, Department of Surgery, Clinical Research Institute, Fukuoka, Japan. tfujii@qmed.hosp.go.jp
Yokoyama
Goro
G
Takahashi
Hiroki
H
Toh
Uhi
U
Kage
Masayoshi
M
Ono
Mayumi
M
Shirouzu
Kazuo
K
Kuwano
Michihiko
M
D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002986:Clinical Trials as Topic; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051840:Y-Box-Binding Protein 1; D000099259:N-myc Downstream-Regulated Gene 1 Protein
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D011493:Protein Kinase C; D051840:Y-Box-Binding Protein 1; D000099259:N-myc Downstream-Regulated Gene 1 Protein; C070856:YBX1 protein, human