Diallyl trisulfide (DATS) is a promising small molecule phytochemical that exhibits in vitro and in vivo activity in multiple preclinical solid tumor models including breast cancer, but the underlying mechanism is not fully understood. We have shown previously that forkhead box Q1 (FoxQ1) transcription factor is a novel target for breast cancer stem-like cells (bCSC) inhibition by DATS. Analysis of the breast TCGA (The Cancer Genome Atlas) data revealed that FoxQ1 expression was positively associated with that of SLC16A1/monocarboxylate transporter 1 (MCT1). Western blot analysis confirmed increased expression of MCT1 protein in SUM159 (basal-like) and MCF-7 cells (luminal-type) stably transfected to overexpress FoxQ1. Furthermore, FoxQ1 was recruited to the promoter of SLC16A1/MCT1. Treatment of SUM159 and MCF-7 cell lines with DATS resulted in suppression of MCT1 protein level that was accompanied by a decrease in intracellular and secreted levels of lactate. Overexpression or knockdown of MCT1 protein failed to alter DATS-mediated inhibition of colony formation or cell migration when compared to corresponding control cells. On the other hand, overexpression of MCT1 protein conferred partial but statistically significant protection against DATS-mediated inhibition of bCSC fraction (CD49f^high/CD44^high and aldehyde dehydrogenase 1 activity). The size of the mammospheres was relatively smaller in the DATS-treated group compared to control group. Inhibition of bCSC upon DATS treatment was augmented by knockdown of the MCT1 protein. In conclusion, the present study reveals that MCT1 is a novel target for bCSC inhibition by DATS treatment.

中文翻译：

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单羧酸转运蛋白 1 是二烯丙基三硫化物抑制乳腺癌干细胞样细胞的新靶点

二烯丙基三硫化物 (DATS) 是一种很有前途的小分子植物化学物质，在包括乳腺癌在内的多种临床前实体瘤模型中表现出体外和体内活性，但其潜在机制尚不完全清楚。我们之前已经证明叉头盒 Q1 (FoxQ1) 转录因子是 DATS 抑制乳腺癌干细胞 (bCSC) 的新靶点。对乳房 TCGA（癌症基因组图谱）数据的分析表明，FoxQ1表达与SLC16A1/单羧酸转运蛋白 1 ( MCT1)呈正相关。蛋白质印迹分析证实，稳定转染过表达 FoxQ1 的 SUM159（基底样）和 MCF-7 细胞（管腔​​型）中 MCT1 蛋白表达增加。此外，FoxQ1被招募到SLC16A1 / MCT1的启动子中。用 DATS 处理 SUM159 和 MCF-7 细胞系会导致 MCT1 蛋白水平受到抑制，同时细胞内和分泌的乳酸水平也会降低。与相应的对照细胞相比，MCT1 蛋白的过表达或敲低未能改变 DATS 介导的集落形成或细胞迁移抑制。另一方面，MCT1 蛋白的过表达提供了部分但具有统计显着性的保护，以防止 DATS 介导的 bCSC 部分（CD49f^高/CD44^高和乙醛脱氢酶 1 活性）的抑制。与对照组相比，DATS 治疗组的微球体尺寸相对较小。通过敲低 MCT1 蛋白，增强了 DATS 处理对 bCSC 的抑制作用。总之，本研究表明 MCT1 是 DATS 治疗抑制 bCSC 的新靶点。