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Breast cancer metastasis is the leading cause of cancer death in women, yet no effective treatment has suppressed breast cancer metastasis. Sulforaphane (SFN), a natural compound derived from broccoli, has shown potential health benefits in many cancers.
However, research on breast cancer metastasis is still insufficient. Here, we showed that SFN, including its two isomers R-SFN and S-SFN, significantly inhibited TGF-pi-induced migration and invasion of breast cancer cells. Proteomic and phosphoproteomic analysis showed that SFN affected cytoskeleton formation. Subsequent experiments confirmed that SFN significantly inhibited actin stress fiber formation induced by TGF-p1 and the expression of proteins associated with actin stress fiber formation, including paxillin, IQGAP1, FAK, PAK2, and ROCK. In addition, SFN directly binds to RAF family proteins (including ARAF, BRAF, and CRAF) and inhibits phosphorylation of MEK and ERK. These in vitro results suggest that SFN targets the RAF/MEK/ERK signaling pathway to inhibit the formation of actin stress fibers, thereby inhibiting breast cancer cell metastasis.
Breast cancer metastasis is the leading cause of cancer death in women, especially triple-negativeNative breast cancer (TNBC) is more aggressive and has a worse prognosis than other types of breast cancer. To date, no effective treatment has prevented breast cancer from metastasizing. Because of the high rate of metastasis, the mortality rate in young women (
Actin stress fibers are a higher order cytoskeletal structure composed of cross-linked bundles of actin filaments that play a critical role in cell migration and invasion. The organization of actin stress fibers promotes cell stiffening and proliferation of preinvasive breast cancer cells9. Numerous studies have demonstrated that the RhoA and Rho kinase (ROCK) signaling pathway is involved in the formation of actin stress fibers. Actin stress fibers are associated with focal adhesions and focal adhesion-associated proteins such as paxillin focl adhesion kinase (FAK) and Ras GTPase-like protein (IQGAP1), which are key regulators of actin cytoskeleton dynamics.
RAF is a serine/threonine-protein kinase that can directly phosphorylate or promote protein phosphorylation of activatedtion of the downstream mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathway. The RAF/MEK/ERK cascade is involved in the regulation of the development and metastasis of several cancers, including lung cancer, liver cancer, and breast cancer. Members of the RAF family include ARAF, BRAF, and CRAF. Recent studies have revealed that a dimerization-dependent mechanism controls the catalytic activation of ARAF, and dimerization of ARAF promotes MAPK pathway activation and cell migration.
Sulforaphane (SFN), a natural compound derived from broccoli/broccoli sprouts, has been shown tosprouts, has shown chemoprotective effects on a variety of cancers, including prostate, lung and colon cancers. Multiple mechanisms of action involved in the anticancer properties of SFN have been reported, including induction of apoptosis, cell cycle arrest, and inhibition of angiogenesis and metastasis. Although SFN has demonstrated potential health benefits in many cancers, there are few studies on the involvement of SFN in breast cancer metastasis. Whether SFN can inhibit breast cancer metastasis and its mechanism are still unclear.
In this study, we aimed to investigate whether SFN has an inhibitory effect on breast cancer cell migration and invasion. We showed that SFN and its two isomers (R-SFN and S-SFN) inhibited transforming growth factor-pi (TGF-pi)-induced migration and invasion in human TNBC cells. The mechanism by which SFN suppresses migration and invasion was further investigated.
Many studies have shown that TGF-pi induced migration and invasion of breast cancer cells. However, the exact mechanism underlying TGF-p1-induced migration and invasion in breast cancer has not been fully elucidated. To determine the effect of SFN on TGF-β1-induced breast cancer cell migration and invasion, we first measured cell viability after SFN treatment (the chemical structure of SFN is shown in Fig. 1a) using the CCK-8 assay. A previous report showed that the IC50 value of SFN varies widely in breast cancer cell lines. Therefore, we treated the cells with different concentrations of SFN from 0.5 to 240 μM for 24 h and then measured the cell viability. As shown in Fig. lb, in MDA-MB-231 cells, SFN has no significant effect on cell viability when the concentration is lower than 30 µM.
However, significant SFN toxicity was observed at SFN concentrations of 60, 120 and 240 µM. In MDA-MB-157 cells, SFN showed no significant effect on cell viability when the concentration was lower than 7.5 µM (Figure 1c). It is well known that when a compound elicits a toxic response on cells, it means that the compound can activate many intracellular signaling pathways. Avoiding toxicity to cells is critical to selectively investigate the antimigratory effects and mechanism(s) of SFN. Therefore, to study the effect of SFN on migration and invasion in two human cells, we used concentrations of 7.5, 15 and 30 µM for MDA-MB-231 cells and 1.9, 3.8 and 7.5 µM for MDA-MB-157 cells. TNBC cell lines MDA-MB-231 and MDA-MB-157.
https://www.nature.com/articles/s41523-022-00402-4
https:// www.carnomed.sk/produkty/sulforafan-extra.htm
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