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

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.

Chrysin inhibit human melanoma A375.S2 cell migration and invasion via affecting MAPK signaling and NF‐κB signaling pathway in vitro

“…Numerous evidences have shown that MMPs have been shown to involve metastasis process including cell adhesion, migration and invasion . MMPs have been shown to be present in melanoma and the inhibition of MMPs which associated with suppressed cancer cell metastasis such as inhibited MMP‐2 could suppressed tumor metastasis . MMP‐9 is closely correlated with tumor metastasis in various cancers and it has been reported that MMP‐9 and other MMPs may be considered as effective targets for anti‐cancer drugs .…”

Phenethyl Isothiocyanate (PEITC) and Benzyl Isothiocyanate (BITC) Inhibit Human Melanoma A375.S2 Cell Migration and Invasion by Affecting MAPK Signaling Pathway In Vitro

“…However, BITC inhibited MMP-2 activity but increased MMP-2 protein levels at all examined doses following 24 or 48 h treatment. It has been reported that MMP-2 is associated with tumor invasion and angiogenesis and that inhibited MMP-2 could suppress tumor metastasis (44,45).…”

Targeting Toll-like receptor 4 with CLI-095 (TAK-242) enhances the antimetastatic effect of the estrogen receptor antagonist fulvestrant on non-small cell lung cancer

“…The results further indicated that treatment with estrogen or ERβ activation also significantly promotes lung cancer cell metastasis by upregulating invasiveness-associated matrix metalloprotease 2 (MMP2) both in vitro and in vivo [13]. Therefore, to markedly depress NSCLC metastasis and to finally detect a new treatment strategy for advanced lung cancer patients, inhibiting the effect induced by estrogen on NSCLC cells is essential.…”

“…Data from urethane-induced primary NSCLC mouse models indicate that the inhibition of ERβ by fulvestrant can significantly reduce lung cancer formation and pleural metastasis [14]. In NSCLC cell lines, proliferation-associated IGF-1 and invasion-associated MMP2 expression levels are downregulated in response to antiestrogens in vitro [13,15]. A clinical study including 26 women with second primary lung cancer among 6,361 diagnosed breast cancer patients provided evidence of a longer cancerspecific survival rate in the patients treated with antiestrogens for breast cancer compared with those treated without antiestrogens [16].…”