Estrogen promotes tumor metastasis via estrogen receptor beta-mediated regulation of matrix-metalloproteinase-2 in non-small cell lung cancer

// Sheng Fan 1 , Yongde Liao 1 , Changyu Liu 1 , Quanfu Huang 1 , Huifang Liang 2 , Bo Ai 1 , Shegnling Fu 1 and Sheng Zhou 3 1 Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China 2 Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China 3 Department of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China Correspondence to: Yongde Liao, email: liaotjxw@126.com Keywords: non-small cell lung cancer (NSCLC), estrogen, estrogen receptor beta (ERβ), matrix-metalloproteinase (MMP), metastasis Received: September 14, 2016     Accepted: February 13, 2017     Published: April 10, 2017 ABSTRACT In non–small cell lung cancer (NSCLC), estrogen significantly promotes NSCLC cell growth via estrogen receptor beta (ERβ). However, the effects by which ERβ contributes to metastasis in NSCLC have not been previously reported. This study aims at defining whether the stimulation of ERβ promotes NSCLC metastasis in vitro and in vivo . Here, Our results showed that estrogen and ERβ agonist enhanced aggressiveness of two lung cancer cell lines (A549 and H1793) and promoted murine lung metastasis formation. ER-inhibitor Fulvestrant treatment or ERβ-knockdown significantly suppressed the migration, invasion and nodule formation of NSCLC cells. The expression level of ERβ protein was analyzed in matched samples of metastatic lymph node and primary tumor tissues from the same individuals, and we found significantly higher levels of ERβ were expressed in lymph node compared to primary tumor tissues. Moreover, Studies on both surgical biopsies and on lung cancer cells revealed that the expression level of ERβ and matrix-metalloproteinase-2 (MMP-2) were associated. Furthermore, inhibition of ERβ resulted in down-regulation of MMP-2 expression. Taken together, our results demonstrate that activation of ERβ in lung cancer cells promotes tumor metastasis through increasing expression of invasiveness-associated MMP-2. These results also highlight the therapeutic potential of inhibition of ERβin the treatment of advanced NSCLC.