title: Activated estrogen receptor-mitogen-activated protein kinases cross talk confer acquired resistance to lapatinib.
abstract: BACKGROUND
  The efficacy of lapatinib is limited by the development of acquired resistance. The aim of this study was to investigate the role of estrogen receptor (ER) signaling compensatory activation in acquired resistance to lapatinib in breast cancer cells BT474 and the related mechanism.
  
  
  METHODS
  Acquired resistant cell model resistant (r)BT474 was generated with an increasing concentration of lapatinib. Real-time polymerase chain reaction and Western blotting were used to determine the changes of human epidermal growth factor receptor (HER)2 and ER pathways in breast cancer cell BT474 after treatment with lapatinib and the distinction between BT474 and rBT474. Methyl thiazolyl tetrazolium and colony formation assays were employed to detect the proliferation of rBT474 and BT474 cells treated with lapatinib and/or an ER inhibitor, fulvestrant, respectively.
  
  
  RESULTS
  Lapatinib could inhibit phosphorylation of HER2 and induce expression of forkhead-box protein O3a and progesterone receptor. Acquired resistant cell model rBT474 could grow in the presence of 5 μM lapatinib, with an apoptosis rate of only 5%. Significant inhibition of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (AKT) pathway and the activation of the mitogen-activated protein kinases (MAPK) and ER pathways were detected in rBT474, compared with BT474. Furthermore, the expressions of Src phosphorylation and caveolin-1 were also upregulated. The viability of rBT474 was markedly suppressed by the lapatinib/fulvestrant combination in vitro, confirmed by the BT474 xenograft model.
  
  
  CONCLUSIONS
  ER signaling compensatory activation may partly contribute to lapatinib acquired resistance in HER2-overexpressing/ERα-positive breast cancer cells, which might be related to PI3K/AKT inhibition and MAPK pathway activation.
authors.affiliation: Department of Thyroid and Breast Surgery, The Tenth People's Hospital of Shanghai, Tongji University Shanghai, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Second Military Medical University Shanghai, China.
authors.forename: Sheng-Sheng
authors.initials: SS
authors.lastname: Yang
authors.affiliation: Department of General Surgery, Shanghai Putuo Hospital, Shanghai University of Traditional Chinese Medicine Shanghai, China.
authors.forename: Pei-Hao
authors.initials: PH
authors.lastname: Yin
authors.affiliation: Department of Thyroid and Breast Surgery, The Tenth People's Hospital of Shanghai, Tongji University Shanghai, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Chang
authors.affiliation: Department of Thyroid and Breast Surgery, The Tenth People's Hospital of Shanghai, Tongji University Shanghai, China.
authors.forename: Lin-Xiang
authors.initials: LX
authors.lastname: Shi
authors.affiliation: Department of Thyroid and Breast Surgery, The Tenth People's Hospital of Shanghai, Tongji University Shanghai, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Fang
authors.affiliation: Department of General Surgery, Changhai Hospital, Second Military Medical University Shanghai, China.
authors.forename: Guo-En
authors.initials: GE
authors.lastname: Fang
keywords: Acquired resistance; ER; HER2; Lapatinib; breast cancer