Effect of lapatinib on the development of estrogen receptor-negative mammary tumors in mice.
Lapatinib, a selective orally available inhibitor of epidermal growth factor receptor (EGFR) and ErbB2 receptor tyrosine kinases, is a promising agent for the treatment of breast cancer. We examined the effect of lapatinib on the development of mammary tumors in MMTV-erbB2 transgenic mice, which express wild-type ErbB2 under the control of the mouse mammary tumor virus promoter and spontaneously develop estrogen receptor (ER)-negative and ErbB2-positive mammary tumors by 14 months of age. Mice were treated from age 3 months to age 15 months with vehicle (n = 17) or lapatinib (30 or 75 mg/kg body weight; n = 16 mice per group) by oral gavage twice daily (6 d/wk). All statistical tests were two-sided. By 328 days after the start of treatment, all 17 (100%) of the vehicle-treated mice vs five (31%) of the 16 mice treated with high-dose lapatinib developed mammary tumors (P < .001). Among MMTV-erbB2 mice treated for 5 months (n = 20 mice per group), those treated with lapatinib had fewer premalignant lesions and noninvasive cancers in their mammary glands than those treated with vehicle (P = .02). Lapatinib also effectively blocked epidermal growth factor-induced signaling through the EGFR and ErbB2 receptors, suppressed cyclin D1 and epiregulin mRNA expression, and stimulated p27 mRNA expression in human mammary epithelial cells and in mammary epithelial cells from mice treated for 5 months with high-dose lapatinib. Thus, cyclin D1, epiregulin, and p27 may represent useful biomarkers of lapatinib response in patients. These data suggest that lapatinib is a promising agent for the prevention of ER-negative breast cancer.
Strecker
Tracy E
TE
Breast Center, Department of Medicine and Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Shen
Qiang
Q
Zhang
Yun
Y
Hill
Jamal L
JL
Li
Yuxin
Y
Wang
Chunyu
C
Kim
Hee-Tae
HT
Gilmer
Tona M
TM
Sexton
Krystal R
KR
Hilsenbeck
Susan G
SG
Osborne
C Kent
CK
Brown
Powel H
PH
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000188:drug therapy; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000188:drug therapy; D019938:Cyclin D1 / Q000187:drug effects / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000187:drug effects / Q000378:metabolism; D066260:Epiregulin; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D000077341:Lapatinib; D008325:Mammary Neoplasms, Experimental / Q000737:chemistry / Q000378:metabolism* / Q000517:prevention & control*; D051379:Mice; D008822:Mice, Transgenic; D011230:Precancerous Conditions / Q000378:metabolism / Q000517:prevention & control*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis*; D011960:Receptors, Estrogen / Q000032:analysis; D015398:Signal Transduction / Q000187:drug effects
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D019938:Cyclin D1; D004815:Epidermal Growth Factor; D066260:Epiregulin; D066246:ErbB Receptors; D000077341:Lapatinib; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; C587880:EREG protein, human; C587881:Ereg protein, mouse; C524056:Erbb2 protein, mouse