Involvement of HDAC3 and HDAC7 in Lapatinib-induced Cell Migration and Invasion

• Main Authors: Min-Hsiang Hsu, 許閔翔
• Other Authors: Wei-Chien Huang
• Format: Others
• Language: zh-TW
• Published: 2011
• Online Access: http://ndltd.ncl.edu.tw/handle/03682327654844784688

碩士 === 中國醫藥大學 === 癌症生物學研究所碩士班 === 99 === Overexpression of HER2/neu, a member of EGF receptor tyrosine kinase family, is found in 20-30% of breast cancer patients and plays a critical role in tumorigenesis. Targeting the tyrosine kinase activity of this receptor by lapatinib (TykerbR, GW-572016), an oral dual inhibitor of EGFR and HER2 tyrosine kinases, has shown encouraging therapeutic benefits for HER2-positive breast cancer patients.Since EGFR expression was detected in up to 80 % of HER2, estrogen receptor (ER), and progesterone receptor (PgR)-negative (triple-negative) breast cancers or other HER2-negative diseases, lapatinib has been tested in HER2-negative patients due to its inhibitory effect on EGFR activity. Unfortunately, lapatinib have shown a lack of dramatic efficacy in overall HER2-negative diseases, and was even found to deteriorate the clinical outcomes in triple-negative and HER2/PgR-negative patients in combination with paclitaxel. This possible and negative influence of lapatinib in HER2-negative diseases might become a major concern for these vigorous clinical trials. Our previous study further revealed that treatment with lapatinib renders triple-negative cells more metastatic via increasing EGFR and COX-2 expressions, providing a possible mechanism explaining the worse clinical observation. However, the molecular mechanism for the induction of EGFR/COX-2 expression by lapatinib remains unclear. Here, our data showed that up-regulation of histone deacetylases(HDAC) 3 and 7, accompanying with the deacetylation of histone H3K9 and H2BK5, were found in the lapatinib-treated MDA-MB-231(231/Lap) cells. Treatment with HDAC inhibitors (SAHA and TSA) or HDAC3 and HDAC7 siRNA dramatically reduced lapatinib-mediated cell migration and invasion through down-regulation of COX-2 expression transcriptionally. Our data further revealed that activations of both NF-κB and MAPK/c-Jun pathways mediated COX-2 gene expression in 231/Lap cells. However, only MAPK/c-Jun but not NF-κB activation was inhibited by HDAC inhibitors, suggesting that lapatinib-induced HDAC3/7 upregulates COX-2 expression through activation of MAPK/c-Jun pathway. Interestingly, treatment with TSA, but not SAHA and HDAC3/7 siRNA,also attenuated the expression of EGFR via up-regulating miR-7 expression, which can target the 3''UTR of EGFR mRNA. These data suggest that inhibitions of HDAC3 and HDAC7 by TSA and SAHA more specifically reduced COX-2 transcription and that inhibitions of other un-identified HDACs by TSA may contribute to the miR-7 expression and subsequent EGFR down-regulation. Unexpectedly, our data further showed that 231/Lap cells are more sensitive to TSA or SAHA than their parental cells. Moreover, silence of HDAC7, but not HDAC3 expression dramatically reduced the viability of 231/Lap cells, suggesting that the status of HDAC7 may be crucial for the antitumor activity of HDAC inhibitor. Our results suggest that HDAC3 and HDAC7 may play a critical role in lapatinib-mediated cell migration through induction of COX-2 expression in a MAPK/c-Jun pathway and that co-treatment with co-treatment with HDAC inhibitors lapatinib may exhibit synergistic therapeutic benefits.