Abstract
HER-2 is an important oncoprotein overexpressed in about 15–25% of breast cancers. We hypothesized that the ability of curcumin to downregulate HER-2 oncoprotein and inhibit the signal transduction pathway of PI3K/Akt, MAPK, and NF-κB activation may be important in the treatment of HER-2-overexpressed breast cancer. To examine the effect of curcumin on breast cancer cells, MCF-7, MDA-MB-231, MCF-10A, BT-474, and SK-BR-3-hr (a herceptin resistant strain from SK-BR-3) cells were used for in vitro analysis. The in vivo effect of curcumin on HER-2-overexpressed breast cancer was investigated with the HER-2-overexpressed BT-474 xenograft model. Cell growth, cell cycle change, the antimobility effect, signal transduction, and xenograft volume analysis between groups treated with herceptin and/or curcumin were tested. Curcumin decreased the cell growth of various breast cancer cell lines (MCF-7, MDA-MB-231, MCF-10A, BT-474, and SK-BR-3-hr). In Western blot analysis, the phosphorylation of Akt, MAPK, and expression of NF-κB were reduced in BT-474 cells, but not in SK-BR-3-hr cells, after treatment with herceptin. When treated with curcumin, the HER-2 oncoprotein, phosphorylation of Akt, MAPK and expression of NF-κB were decreased in both BT-474 and SK-BR-3-hr cells. In the BT-474 xenograft model, though not as much as herceptin, curcumin did effectively decrease the tumor size. The combination of curcumin with herceptin was not better than herceptin alone; however, the combination of taxol and curcumin had an antitumor effect comparable with taxol and herceptin. The results suggested that curcumin has potential as a treatment for HER-2-overexpressed breast cancer.
Highlights
Around 15–25% of breast cancers are noted to overexpress the human epithelial growth factor receptor 2 (HER-2) [1,2,3], patients with HER-2 overexpression were associated with a poor prognosis, more disease relapse, and distant metastasis [3,4,5,6]
In examining the effect of curcumin treatment on these cell lines, we found that the cell proliferations of these five cell lines (MCF-7, BT-474, SK-BR-3-hr, MCF-10A, and MDAMB-231) were all decreased after treatment with curcumin, with different sensitivities (Figure 2(b))
This study was designed to test the efficacy of curcumin in HER-2-overexpressed breast cancer, with a direct comparison with herceptin in the in vitro cell line and in vivo xenograft animal model
Summary
Around 15–25% of breast cancers are noted to overexpress the human epithelial growth factor receptor 2 (HER-2) [1,2,3], patients with HER-2 overexpression were associated with a poor prognosis, more disease relapse, and distant metastasis [3,4,5,6]. Herceptin (generic name: Trastuzumab), which effectively inhibits the HER-2-related PI3k/Akt and MAPK pathways, is the first targeted therapeutic agent developed and approved for the treatment of patients with HER-2overexpressed breast cancer [7,8,9,10,11,12]. Despite the success of herceptin, a significant proportion of HER-2-positive breast cancer patients responded poorly to the treatment [13, 14]. The ability of curcumin to downregulate EGFR [19, 21, 22] and HER-2 [23] oncoproteins and affect the PI3K/Akt [24] and MAPK [25] pathways, with which herceptin interfered, raised interest in the potential utility of curcumin in the treatment of HER-2-positive breast cancer
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