Compensatory activation of estrogen receptor α signaling in acquired resistance to lapatinib of HER2-overexpressing/ERα-positive breast cancer cells
10.3724/Sp.J.1008.2013.00616
- Author:
Zhe LI
1
Author Information
1. Department of Thyroid and Breast Surgery, Tenth Hospital, Tongli University School of Medicine
- Publication Type:Journal Article
- Keywords:
Breast neoplasms;
erbB-2 receptor;
Estrogen receptor alpha;
Lapatinib;
Neoplasm drug resistance
- From:
Academic Journal of Second Military Medical University
2013;34(6):616-622
- CountryChina
- Language:Chinese
-
Abstract:
Objective To investigate the role of compensatory activation of estrogen receptor α (ERα) signaling in acquired resistance to lapatinib of breast cancer cells BT474 and the related mechanism. Methods Real-time PCR and Western blotting analysis were used to determine the changes of HER2 and ERα pathways in BT474 cells treated by lapatinib. Acquired resistant model of rBT474 cellswas induced with increasing concentrations of lapatinib (from 0. 25 μmol/L to 5 μmol/L); the apoptosis in rBT474 cells was determined by flow cytometry. Western blotting analysis was used to evaluate the differences between BT474 and rBT474 in the HER2 and ER pathways. The growth of rBT474 cells treated by lapatinib and/or fulvestrant was detected by MTT assay, andcolony formation was used to observe the possibility of preventing acquired resistance to lapatinib in BT474 cells by double targets therapy. Results The results of real-time PCR and Western blotting analysis showed that Lapatinib inhibited phosphorylation of HER2 and induced expression of forkhead-box protein O 3A (F0X03a) and progesterone receptor (PR) in BT474 cells. Acquired resistance cell model of rBT474 was established in a 5 μmol/L lapatinib condition. Western blotting analysis showed that the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway was inhibited in rBT474 cells compared with that in the BT474 cells, while the mitogen-activated protein kinase (MAPK) pathways, especially the ER pathway, were activated in the BT474 cells. MTT results showed that, Lapatinib combined with fulvestrant had a significantly greater inhibition on rBT474 cell vitality compared with lapatinib alone (P<0. 01). Colony formation results also showed that combination of lapatinib and fulvestrant had a significantly greater inhibition effect against colon formation of BT474 cells compared with each drug alone and DMSO (P<0. 01), showing a possible prevention ability against acquired resistance. Conclusion Compensatory activation of estrogen receptor a signaling might be one of the mechanisms of acquired resistance to lapatinib in HER2-overexpressing/ERcrpositive breast cancer cells, and inhibition of PI3K/AKT and activation of MAPK might be the main reason for compensatory activation of ERα.
