title: SRC family kinases as novel therapeutic targets to treat breast cancer brain metastases.
abstract: Despite better control of early-stage disease and improved overall survival of patients with breast cancer, the incidence of life-threatening brain metastases continues to increase in some of these patients. Unfortunately, other than palliative treatments there is no effective therapy for this condition. In this study, we reveal a critical role for Src activation in promoting brain metastasis in a preclinical model of breast cancer and we show how Src-targeting combinatorial regimens can treat HER2(+) brain metastases in this model. We found that Src was hyperactivated in brain-seeking breast cancer cells derived from human cell lines or from patients' brain metastases. Mechanistically, Src activation promoted tumor cell extravasation into the brain parenchyma via permeabilization of the blood-brain barrier. When combined with the EGFR/HER2 dual-targeting drug lapatinib, an Src-targeting combinatorial regimen prevented outgrowth of disseminated breast cancer cells through the induction of cell-cycle arrest. More importantly, this combinatorial regimen inhibited the outgrowth of established experimental brain metastases, prolonging the survival of metastases-bearing mice. Our results provide a rationale for clinical evaluation of Src-targeting regimens to treat patients with breast cancer suffering from brain metastasis.
authors.affiliation: Authors' Affiliations: Departments of Molecular and Cellular Oncology, Neurosurgery, and Pathology, The University of Texas MD Anderson Cancer Center; Cancer Biology Program, Graduate School of Biomedical Sciences-Houston, Houston, Texas; Women's Cancers Section, Laboratory of Molecular Pharmacology, National Cancer Institute, Bethesda, Maryland; and Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana.
authors.forename: Siyuan
authors.initials: S
authors.lastname: Zhang
authors.forename: Wen-Chien
authors.initials: WC
authors.lastname: Huang
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.forename: Chenyu
authors.initials: C
authors.lastname: Zhang
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Lowery
authors.forename: Zhaoxi
authors.initials: Z
authors.lastname: Ding
authors.forename: Hua
authors.initials: H
authors.lastname: Guo
authors.forename: Hai
authors.initials: H
authors.lastname: Wang
authors.forename: Suyun
authors.initials: S
authors.lastname: Huang
authors.forename: Aysegul A
authors.initials: AA
authors.lastname: Sahin
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Aldape
authors.forename: Patricia S
authors.initials: PS
authors.lastname: Steeg
authors.forename: Dihua
authors.initials: D
authors.lastname: Yu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects; D015153:Blotting, Western; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D001932:Brain Neoplasms / Q000201:enzymology / Q000517:prevention & control* / Q000556:secondary; D001943:Breast Neoplasms / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D017097:Electric Impedance; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D000077341:Lapatinib; D051379:Mice; D040081:Protein Array Analysis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D066246:ErbB Receptors; D000077341:Lapatinib; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D019061:src-Family Kinases; C512478:EGFR protein, human
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