Effect of epidermal growth factor receptor inhibitor on development of estrogen receptor-negative mammary tumors.
BACKGROUND
Although antiestrogens have been effective in preventing estrogen receptor (ER)-positive breast cancer, chemopreventive agents are still needed to prevent ER-negative breast cancer. Tyrosine kinase inhibitors are promising agents for the treatment and prevention of human cancers. ZD1839 (gefitinib or Iressa) is an orally active epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that blocks signal transduction pathways in epithelial cells. We examined whether ZD1839 blocks signal transduction and prevents the development of ER-negative breast cancer.


METHODS
The ability of ZD1839 to block signal transduction in normal, immortalized, and malignant breast cells was assessed by western blotting with specific antibodies to detect phosphorylation of cytoplasmic signaling molecules. The effect of ZD1839 on growth of these breast cells was assessed with anchorage-dependent and anchorage-independent growth assays. Its effect on ER-negative mammary tumorigenesis was assessed in MMTV-erbB2 transgenic mice. All statistical tests were two-sided.


RESULTS
ZD1839 suppressed the phosphorylation of EGFR and mitogen-activated protein kinase in normal and malignant breast cells. ZD1839 treatment statistically significantly suppressed mammary tumorigenesis in MMTV-erbB2 transgenic mice; median time to tumor development was approximately 230 days in vehicle-treated mice and more than 310 days in mice treated with ZD1839 at 100 mg/kg (P<.001). ZD1839 reduced proliferation of normal breast cells by 20.3% (95% confidence interval [CI] = -13.7% to 44.2%) and of tumor cells by 42.0% (95% CI = 20.2% to 58.2%). ZD1839 also increased expression of the cell cycle regulator p27 in normal mammary tissue by 48.7% (95% CI = 27.0% to 74.2%) and in tumor tissue by 50.3% (95% CI = 35.8% to 66.7%).


CONCLUSIONS
This study appears to provide the preclinical rationale for the development of these EGFR tyrosine kinase inhibitors for the prevention of human breast cancer.
Lu
Chunhua
C
Department of Medicine, Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.
Speers
Corey
C
Zhang
Yun
Y
Xu
Xiaochun
X
Hill
Jamal
J
Steinbis
Emily
E
Celestino
Joseph
J
Shen
Qiang
Q
Kim
Heetae
H
Hilsenbeck
Susan
S
Mohsin
Syed K
SK
Wakeling
Alan
A
Osborne
C Kent
CK
Brown
Powel H
PH
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000517:prevention & control*; D002460:Cell Line; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004847:Epithelial Cells; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018734:Genes, erbB-2 / Q000187:drug effects; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000032:analysis; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D009124:Muscle Proteins; D010766:Phosphorylation / Q000187:drug effects; D011230:Precancerous Conditions / Q000188:drug therapy / Q000517:prevention & control; D011799:Quinazolines / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
D016588:Anticarcinogenic Agents; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D008840:Microfilament Proteins; D009124:Muscle Proteins; D011799:Quinazolines; D011960:Receptors, Estrogen; C058992:Tagln protein, mouse; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases; D000077156:Gefitinib