title: Short-term early exposure to lapatinib confers lifelong protection from mammary tumor development in MMTV-erbB-2 transgenic mice.
abstract: Although chemopreventative agents targeting the estrogen/estrogen receptor (ER) pathway have been effective for ER+breast cancers, prevention of hormone receptor-negative breast cancers, such as Her2/erbB-2+breast cancers, remains a significant issue. Previous studies have demonstrated that administration of EGFR/erbB-2-targeting lapatinib to MMTV-erbB-2 transgenic mice inhibited mammary tumor development. The prevention, however, was achieved by prolonged high dose exposure. The tolerance to high dose/long-term drug administration may hinder its potential in clinical settings. Therefore, we aimed to test a novel, short-term chemopreventative strategy using lapatinib during the premalignant risk window in MMTV-erbB-2 mice.
  
  
  
  We initially treated cultured cells with lapatinib to explore the anti-proliferative effects of lapatinib in vitro. We used a syngeneic tumor graft model to begin exploring the in vivo anti-tumorigenic effects of lapatinib in MMTV-erbB-2 mice. Then, we tested the efficacy of brief exposure to lapatinib (100 mg/kg/day for 8 weeks), beginning at 16 weeks of age, in the prevention of mammary tumor development in MMTV-erbB-2 mice.
  
  
  
  In the syngeneic tumor transplant model, we determined that lapatinib significantly inhibited tumor cell proliferation. Furthermore, we demonstrated that short-term lapatinib exposure resulted in life-long protective effects, as supported by increased tumor latency in lapatinib-treated mice compared to the control mice. We further established that delayed tumor development in the treated mice was preceded by decreased BrdU nuclear incorporation and inhibited mammary morphogenesis. Molecular analysis indicated that lapatinib inhibited phosphorylation and expression of EGFR, erbB-3, erbB-2, Akt1, and Erk1/2 in premalignant mammary tissues. Also, lapatinib drastically inhibited the phosphorylation and expression of ERα and the transcription of ER target genes in premalignant mammary tissues. We also determined that lapatinib suppressed the stemness of breast cancer cell lines, as evidenced by decreased tumorsphere formation and ALDH+cell populations.
  
  
  
  Taken together, these data demonstrate that brief treatment with EGFR/erbB-2-targeting agents before the onset of tumors may provide lifelong protection from mammary tumors, through the concurrent inhibition of erbB-2 and ER signaling pathways and consequential reprogramming. Our findings support further clinical testing to explore the benefit of shorter lapatinib exposure in the prevention of erbB-2-mediated carcinogenesis.
authors.affiliation: Julius L. Chambers Biomedical/Biotechnology Research Institute, Department of Biological and Biomedical Sciences, North Carolina Central University, 500 Laureate Way, Room 4301, Kannapolis, NC, 28081, USA.|Department of Oncology, First Affiliated Hospital of Henan University of Sciences and Technology, Luoyang, China.
authors.forename: Zhikun
authors.initials: Z
authors.lastname: Ma
authors.affiliation: Julius L. Chambers Biomedical/Biotechnology Research Institute, Department of Biological and Biomedical Sciences, North Carolina Central University, 500 Laureate Way, Room 4301, Kannapolis, NC, 28081, USA.
authors.forename: Amanda B
authors.initials: AB
authors.lastname: Parris
authors.affiliation: Julius L. Chambers Biomedical/Biotechnology Research Institute, Department of Biological and Biomedical Sciences, North Carolina Central University, 500 Laureate Way, Room 4301, Kannapolis, NC, 28081, USA.
authors.forename: Zhengzheng
authors.initials: Z
authors.lastname: Xiao
authors.affiliation: Julius L. Chambers Biomedical/Biotechnology Research Institute, Department of Biological and Biomedical Sciences, North Carolina Central University, 500 Laureate Way, Room 4301, Kannapolis, NC, 28081, USA.
authors.forename: Erin W
authors.initials: EW
authors.lastname: Howard
authors.affiliation: Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.
authors.forename: Stanley D
authors.initials: SD
authors.lastname: Kosanke
authors.affiliation: Department of Oncology, First Affiliated Hospital of Henan University of Sciences and Technology, Luoyang, China.
authors.forename: Xiaoshan
authors.initials: X
authors.lastname: Feng
authors.affiliation: Julius L. Chambers Biomedical/Biotechnology Research Institute, Department of Biological and Biomedical Sciences, North Carolina Central University, 500 Laureate Way, Room 4301, Kannapolis, NC, 28081, USA. xyang@nccu.edu.|Department of Oncology, First Affiliated Hospital of Henan University of Sciences and Technology, Luoyang, China. xyang@nccu.edu.
authors.forename: Xiaohe
authors.initials: X
authors.lastname: Yang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004334:Drug Administration Schedule; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D000077341:Lapatinib; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines / Q000008:administration & dosage* / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D066246:ErbB Receptors; D000077341:Lapatinib; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; C541485:EGFR protein, mouse; C508053:ERBB2 protein, human; C000607800:ErbB3 protein, mouse; C524056:Erbb2 protein, mouse
keywords: Crosstalk; EGFR; ErbB-2/Her2; Estrogen receptor (ER); Lapatinib; MMTV-erbB-2 transgenic mice