Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
Clinical Research Laboratory, Uijeongbu St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
Cancer Genomics Proteomics. 2024 Sep-Oct;21(5):511-522. doi: 10.21873/cgp.20468.
BACKGROUND/AIM: Interferon-induced trans-membrane protein 1 (IFITM1) is known to be involved in breast cancer progression. We aimed to investigate its role in estrogen receptor (ER)-positive breast cancer cells with wild-type p53 and tamoxifen-resistant breast cancer cells.
The ER-positive breast cancer cell lines, MCF-7 with wild-type p53 and T47D with mutant p53, were used. We established an MCF-7-derived tamoxifen-resistant cell line (TamR) by long-term culture of MCF-7 cells with 4-hydroxytamoxifen.
IFITM1 inhibition in MCF-7 cells significantly decreased cell growth and migration. MCF-7 cells with suppression of IFITM1 using siRNA or ruxolitinib showed reduced cell viability after tamoxifen treatment compared with that in the control MCF-7 cells. Unexpectedly, mRNA and protein levels of IFITM1 were decreased in TamR cells compared with those in MCF-7 cells. TamR cells with suppression of IFITM1 using siRNA or ruxolitinib showed no change in cell viability after treatment with tamoxifen. P53 knockdown using siRNA reduced the mRNA levels of IRF9 and increased mRNA and protein levels of SOCS3 in MCF-7 cells, suggesting that loss or mutation of p53 can affect the induction of IFITM1 via the JAK/STAT signaling pathway in breast cancer. Furthermore, MCF-7 cells with p53 knockdown using siRNA showed no decrease in cell viability after tamoxifen treatment or IFITM1 inhibition, indicating that p53 status may be important for cell death after tamoxifen treatment or IFITM1 inhibition.
IFITM1 inhibition may enhance the sensitivity to tamoxifen based on p53-dependent enhancement of IFN signaling in wild-type p53, ER-positive breast cancer cells.
背景/目的：干扰素诱导跨膜蛋白 1（IFITM1）已知参与乳腺癌的进展。我们旨在研究其在野生型 p53 且雌激素受体（ER）阳性和对他莫昔芬耐药的乳腺癌细胞中的作用。
使用 ER 阳性乳腺癌细胞系 MCF-7（野生型 p53）和 T47D（突变型 p53）。我们通过 MCF-7 细胞的长期培养建立了 MCF-7 衍生的对他莫昔芬耐药的细胞系（TamR），并用 4-羟基他莫昔芬处理。
IFITM1 抑制在 MCF-7 细胞中显著降低细胞生长和迁移。与对照 MCF-7 细胞相比，用 siRNA 或 ruxolitinib 抑制 IFITM1 的 MCF-7 细胞在用他莫昔芬处理后显示出降低的细胞活力。出乎意料的是，与 MCF-7 细胞相比，TamR 细胞中的 IFITM1 mRNA 和蛋白水平降低。用 siRNA 或 ruxolitinib 抑制 IFITM1 的 TamR 细胞在用他莫昔芬处理后细胞活力没有变化。用 siRNA 敲低 p53 降低了 MCF-7 细胞中 IRF9 的 mRNA 水平，并增加了 SOCS3 的 mRNA 和蛋白水平，表明 p53 的缺失或突变可以通过 JAK/STAT 信号通路影响乳腺癌中 IFITM1 的诱导。此外，用 siRNA 敲低 p53 的 MCF-7 细胞在用他莫昔芬处理或 IFITM1 抑制后细胞活力没有降低，表明 p53 状态可能对他莫昔芬治疗或 IFITM1 抑制后的细胞死亡很重要。
IFITM1 抑制可能通过增强野生型 p53 中 IFN 信号的 JAK/STAT 依赖性增强来提高对他莫昔芬的敏感性，在 ER 阳性乳腺癌细胞中。
