Abstract
Aberrant transforming growth factor-β (TGF-β) plays an important role in the development of cancer such as tumor metastasis and invasion. TGF-β-responsive gene signature is highly activated in chemotherapy-treated triple negative breast cancer (TNBC). Here, we investigated the effect of zerumbone (ZER) on TGF-β1 signaling pathway and tumorigenecity of TNBC cells. Our results showed that the level of TGF-β1 mRNA expression and cell invasiveness were higher in TNBC cells than in non-TNBC cells. On the other hand, the cell motility of TNBC cells was completely suppressed by LY2109761, a novel selective TGF-β receptor type I/II (TβRI/II) dual inhibitor. In addition, FN and MMP-2 expression, which play an important role on cell motility in various cancer cells, were dose-dependently decreased by LY2109761. TGF-β1 increased FN, MMP-2 and MMP-9 expression in HCC1806 TNBC cells. TGF-β1-induced MMP-9 expression was decreased by both a MEK inhibitor, UO126, and a smad3 inhibitor, SIS3. Induction of FN and MMP-2 by TGF-β1 was just decreased by SIS3. Overexpression of smad3 significantly increased FN, MMP-2, and MMP-9 expression. Interestingly, ZER significantly suppressed TGF-β1-induced FN, MMP-2, and MMP-9 expression in HCC1806 cells. In addition, ZER completely decreased TGF-β1-induced the phosphorylation of smad3. Finally, we observed that ZER suppressed the tumorigenecity such as tumor volume, weight, Ki67 expression, and metastasis in TNBC cells xenograft models. Taken together, we demonstrated that ZER suppresses TGF-β1-induced FN, MMP-2, and MMP-9 expression through the inactivation of smad3 and inhibits the tumorigenecity of TNBC cells. Therefore, we suggest that ZER may act as a promising drug for treatment of TNBC.
Highlights
Triple-negative breast cancer (TNBC) accounts for 15% to 20% of breast cancers and is a heterogeneous disease [1, 2]
Our results showed that TGF-β1 mRNA and protein expression was significantly increased in triple negative breast cancer (TNBC) cells compared with non-TNBC cells (Figure 1A and 1B)
Plasma www.impactjournals.com/oncotarget levels of transforming growth factor-β (TGF-β) are elevated in patients with breast cancer whereas after surgical removal of the primary tumor, highly expressed TGF-β1 levels normalize in the majority of patients [33, 34]
Summary
Triple-negative breast cancer (TNBC) accounts for 15% to 20% of breast cancers and is a heterogeneous disease [1, 2]. Of all subtypes of breast cancer, TNBC tends to occur in younger age with pre-menopausal women and occurs more frequently in African American women [4, 5]. TNBC is typically associated with poor prognosis when compared with other breast cancer subtypes [4,5,6,7]. Highly recurrent rate of TNBC is associated with aggressive phenotype, chemotherapy resistance, and the lack of clinically therapeutic targets [6, 8]. No therapeutic agents have been clinically approved for treatment of TNBC. Many researchers focus on the development of new therapeutic agents for treatment of TNBC
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