Elson Daniel J, Nguyen Bach D, Korjeff Nicholas A, Wilferd Sierra F, Puig-Sanvicens Veronica, Sang Jang Hyo, Bernales Sebastian, Chakravarty Sarvajit, Belmar Sebastián, Ureta Gonzalo, Finlay Darren, Plaisier Christopher L, Kolluri Siva K
Cancer Research Laboratory, Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331, United States.
School of Biological and Health Systems Engineering, Arizona State University, Tempe, AZ 85287, United States.
Biochem Pharmacol. 2023 Sep;215:115706. doi: 10.1016/j.bcp.2023.115706. Epub 2023 Jul 26.
Triple-negative breast cancer (TNBC) represents around 15% of the 2.26 million breast cancers diagnosed worldwide annually and has the worst outcome. Despite recent therapeutic advances, there remains a lack of targeted therapies for this breast cancer subtype. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor with biological roles in regulating development, xenobiotic metabolism, cell cycle progression and cell death. AhR activation by select ligands can promote tumor suppression in multiple cancer types. AhR can negatively regulate the activity of different oncogenic signaling pathways and can directly upregulate tumor suppressor genes such as p27. To determine the role of AhR in TNBC, we generated AhR-deficient cancer cells and investigated the impact of AhR loss on TNBC cell growth phenotypes. We found that AhR-deficient MDA-MB-468 TNBC cells have increased proliferation and formed significantly more colonies compared to AhR expressing cells. These cells without AhR expression grew aggressively in vivo. To determine the molecular targets driving this phenotype, we performed transcriptomic profiling in AhR expressing and AhR knockout MDA-MB-468 cells and identified tyrosine receptor kinases, as well as other genes involved in proliferation, survival and clonogenicity that are repressed by AhR. In order to determine therapeutic targeting of AhR in TNBC, we investigated the anti-cancer effects of the novel AhR ligand 11-chloro-7H-benzimidazo[2,1-a]benzo[de]iso-quinolin-7-one (11-Cl-BBQ), which belongs to a class of high affinity, rapidly metabolized AhR ligands called benzimidazoisoquinolines (BBQs). 11-Cl-BBQ induced AhR-dependent cancer cell-selective growth inhibition and strongly inhibited colony formation in TNBC cells.
三阴性乳腺癌（TNBC）约占全球每年诊断出的226万例乳腺癌的15%，且预后最差。尽管近期治疗取得了进展，但针对这种乳腺癌亚型的靶向治疗仍然缺乏。芳烃受体（AhR）是一种配体激活的转录因子，在调节发育、外源性物质代谢、细胞周期进程和细胞死亡方面具有生物学作用。特定配体激活AhR可在多种癌症类型中促进肿瘤抑制。AhR可负向调节不同致癌信号通路的活性，并可直接上调肿瘤抑制基因如p27。为了确定AhR在TNBC中的作用，我们构建了AhR缺陷癌细胞，并研究了AhR缺失对TNBC细胞生长表型的影响。我们发现，与表达AhR的细胞相比，AhR缺陷的MDA-MB-468 TNBC细胞增殖增加，形成的集落明显更多。这些不表达AhR的细胞在体内生长旺盛。为了确定驱动这种表型的分子靶点，我们对表达AhR和AhR基因敲除的MDA-MB-468细胞进行了转录组分析，鉴定出酪氨酸受体激酶以及其他参与增殖、存活和克隆形成且被AhR抑制的基因。为了确定TNBC中AhR的治疗靶点，我们研究了新型AhR配体11-氯-7H-苯并咪唑[2,1-a]苯并[de]异喹啉-7-酮（11-Cl-BBQ）的抗癌作用，该配体属于一类高亲和力、快速代谢的AhR配体，称为苯并咪唑异喹啉（BBQs）。l1-Cl-BBQ诱导AhR依赖性癌细胞选择性生长抑制，并强烈抑制TNBC细胞中的集落形成。
