Poole Vikki L, Alshahrani Mohammed M, Manivannan Selvambigai, Landa Iñigo, Hariharan Aditi, Thompson Rebecca J, Kocbiyik Merve, Thornton Caitlin E M, Brookes Katie, Fletcher Alice, Boelaert Kristien, Read Martin L, McCabe Christopher J, Smith Vicki E
Department of Metabolism & Systems Science (MSS) and Centre for Endocrinology, Diabetes and Metabolism (CEDAM), College of Medicine and Health, University of Birmingham, Birmingham, UK.
Institut Gustave Roussy, Inserm U981, Villejuif, France.
Endocr Relat Cancer. 2025 Aug 20;32(8). doi: 10.1530/ERC-24-0312. Print 2025 Aug 1.
Sodium iodide symporter (NIS) expression in breast cancer renders radioiodide (RAI) a promising treatment modality. However, insufficient functional NIS within the plasma membrane limits RAI uptake (RAIU). We aimed to elucidate NIS regulatory mechanisms that impede RAIU in breast cancer and identify molecular targets for stimulating RAI-avidity in breast tumours. Mechanistic interaction between pituitary tumor-transforming gene-binding factor (PBF/PTTG1IP) and NIS was investigated through NanoBiT, co-immunoprecipitation, immunofluorescent microscopy, subcellular localisation and RAIU assays utilising wild-type and CRISPR-Cas9 PBF knockout breast cancer cells. In breast cancer cells, NIS:PBF interaction resulted in diminished RAIU, reversible through reduced PBF phosphorylation by the Src inhibitor dasatinib. Src overexpression diminished RAIU in a PBF-dependent manner that was mediated by Src myristoylation by N-myristoyltransferase 1 (NMT1). NMT1 inhibition significantly enhanced RAIU via Src and PBF in breast and thyroid cancer cells. Bioinformatic analyses revealed clinical associations between high Src and NMT1 expression and increased tumour recurrence in RAI-treated thyroid cancers indicating RAI-resistance. In breast cancer, high PBF and Src expression was associated with the more aggressive tumours that are most likely to benefit from targeted RAI therapy. We describe a new NIS regulatory pathway in breast cancer cells via Src myristoylation and PBF phosphorylation and show that the same pathway exists in thyroid cells, the canonical setting for the exploitation of NIS function. These findings reveal that PBF interaction with NIS may be modulated by Src, which in turn is susceptible to NMT inhibition, and suggest that targeting NMT1 may represent an innovative approach for augmenting RAI-avidity in breast cancer.
乳腺癌中钠碘同向转运体（NIS）的表达使放射性碘（RAI）成为一种有前景的治疗方式。然而，质膜内功能性NIS不足限制了RAI摄取（RAIU）。我们旨在阐明阻碍乳腺癌中RAIU的NIS调节机制，并确定刺激乳腺肿瘤中RAI亲和力的分子靶点。通过NanoBiT、免疫共沉淀、免疫荧光显微镜、亚细胞定位以及利用野生型和CRISPR-Cas9 PBF基因敲除乳腺癌细胞进行的RAIU测定，研究了垂体肿瘤转化基因结合因子（PBF/PTTG1IP）与NIS之间的机制性相互作用。在乳腺癌细胞中，NIS与PBF的相互作用导致RAIU降低，通过Src抑制剂达沙替尼减少PBF磷酸化可使其逆转。Src过表达以PBF依赖的方式降低RAIU，这是由N-肉豆蔻酰转移酶1（NMT1）对Src进行肉豆蔻酰化介导的。NMT1抑制通过Src和PBF显著增强乳腺癌和甲状腺癌细胞中的RAIU。生物信息学分析揭示了高Src和NMT1表达与接受RAI治疗的甲状腺癌肿瘤复发增加之间的临床关联，表明存在RAI抵抗。在乳腺癌中，高PBF和Src表达与最有可能从靶向RAI治疗中获益的侵袭性更强的肿瘤相关。我们描述了一种通过Src肉豆蔻酰化和PBF磷酸化在乳腺癌细胞中的新NIS调节途径，并表明甲状腺细胞中也存在相同途径，甲状腺细胞是利用NIS功能的典型环境。这些发现揭示了PBF与NIS的相互作用可能受Src调节，而Src又易受NMT抑制影响，并表明靶向NMT1可能是增强乳腺癌中RAI亲和力的一种创新方法。
