Choline kinase activation is a critical requirement for the proliferation of primary human mammary epithelial cells and breast tumor progression.
Breast cancer is still one of the most important tumors among women in industrialized countries. Improvement in both understanding the molecular events associated with the disease and the development of new additional treatments is still an important goal to be achieved. Choline kinase (ChoK) is increased in human mammary tumors with high incidence, and this activation is associated with clinical variable indicators of greater malignancy. Here, we have investigated the role of ChoK in the development of breast cancer and found that ChoK is both necessary and sufficient for growth factor-induced proliferation in primary human mammary epithelial cells and an absolute requirement for the specific mitogenic response to heregulin in breast tumor-derived cells. These results demonstrate that ChoK plays an essential role in both normal human mammary epithelial cell proliferation and breast tumor progression. Furthermore, inhibition of ChoK shows a strong in vivo antitumor activity against human breast cancer xenografts. Thus, ChoK constitutes a novel bona fide molecular target for the treatment of breast cancer patients.
Ramírez de Molina
Ana
A
Department of Molecular and Cellular Biology of Cancer, Translational Oncology Unit, Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Cicutíficas, Madrid, Spain.
Báñez-Coronel
Mónica
M
Gutiérrez
Ruth
R
Rodríguez-González
Agustín
A
Olmeda
David
D
Megías
Diego
D
Lacal
Juan Carlos
JC
D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002797:Choline Kinase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D005260:Female; D006801:Humans; D042361:Mammary Glands, Human / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D008819:Mice, Nude; D020890:Neuregulin-1 / Q000494:pharmacology; D010767:Phosphorylcholine / Q000378:metabolism; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
D004791:Enzyme Inhibitors; D020890:Neuregulin-1; D010767:Phosphorylcholine; D002797:Choline Kinase