Epidermal growth factor receptor tyrosine kinase inhibitor reverses mesenchymal to epithelial phenotype and inhibits metastasis in inflammatory breast cancer.
OBJECTIVE
Inflammatory breast cancer (IBC) is a rare but aggressive type of advanced breast cancer. Epidermal growth factor receptor (EGFR) expression is an independent poor prognostic factor in IBC. The purpose of this study was to determine the effect on IBC tumorigenicity and metastasis of blocking the EGFR pathway.


METHODS
IBC cell lines, which express high level of EGFR, were treated with EGFR small interfering RNA and with the EGFR tyrosine kinase inhibitor erlotinib. The role of EGFR in IBC cell proliferation, motility, invasiveness, and change of the expression levels of epithelial-mesenchymal transition markers was examined. The role of extracellular signal-regulated kinase (ERK)-1/2 in erlotinib activity was also studied. The activity of erlotinib in tumor growth and metastasis was examined in an orthotopic xenograft model of IBC.


RESULTS
Erlotinib inhibited proliferation and anchorage-independent growth of IBC cells, and this inhibition was ERK dependent. Erlotinib inhibited cell motility and invasiveness and reversed the mesenchymal phenotype of IBC cells to epithelial phenotype in three-dimensional culture. Erlotinib dramatically inhibited IBC tumor growth in a xenograft model. Interestingly, erlotinib inhibited spontaneous lung metastasis, even at a low dose that had no significant effect on primary tumor growth. These erlotinib-treated tumors were converted to epithelial phenotype from mesenchymal phenotype.


CONCLUSIONS
The EGFR pathway is involved in tumor growth and metastasis of IBC. Targeting EGFR through the ERK pathway may represent an effective therapeutic approach to suppress tumorigenicity and prevent metastasis in EGFR-expressing IBC.
Zhang
Dongwei
D
Breast Cancer Translational Research Laboratory, Department of Breast Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
LaFortune
Tiffany A
TA
Krishnamurthy
Savitri
S
Esteva
Francisco J
FJ
Cristofanilli
Massimo
M
Liu
Ping
P
Lucci
Anthony
A
Singh
Balraj
B
Hung
Mien-Chie
MC
Hortobagyi
Gabriel N
GN
Ueno
Naoto T
NT
D000230:Adenocarcinoma / Q000188:drug therapy; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D004848:Epithelium / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D000069347:Erlotinib Hydrochloride; D006801:Humans; D007249:Inflammation / Q000188:drug therapy*; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D008297:Male; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D034741:RNA, Small Interfering; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors