NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Immunology and Cancer Pharmacology Group, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Sci Transl Med. 2021 Mar 24;13(586). doi: 10.1126/scitranslmed.abb2914.
Most basal-like breast cancers (BLBCs) are triple-negative breast cancers (TNBCs), which have the worst prognosis and distant metastasis-free survival among breast cancer subtypes. Now, no targeted therapies are available for patients with BLBC due to the lack of reliable and effective molecular targets. Here, we performed the BLBC tissue microarray-based immunohistochemical analysis and showed that Faciogenital Dysplasia 5 (FGD5) abundance is associated with poor prognosis in BLBCs. deletion decreased the proliferation, invasion, and tumorsphere formation capacity of BLBC cells. Furthermore, genetic inhibition of in mouse mammary epithelial cells attenuated BLBC initiation and progression by reducing the self-renewal ability of tumor-initiating cells. In addition, FGD5 abundance was positively correlated with the abundance of epidermal growth factor receptor (EGFR) in BLBCs. ablation decreased EGFR abundance by reducing EGFR stability in TNBC cells in 2D and 3D culture conditions. Mechanistically, FGD5 binds to EGFR and interferes with basal EGFR ubiquitination and degradation induced by the E3 ligase ITCH. Impaired EGFR degradation caused BLBC cell proliferation and promoted invasive properties and self-renewal. To verify the role of the FGD5-EGFR interaction in the regulation of EGFR stability, we screened a cell-penetrating α-helical peptide PER3 binding with FGD5 to disrupt the interaction. Treatment of BLBC patient-derived xenograft-bearing mice with the peptide PER3 disrupting the FGD5-EGFR interaction either with or without chemotherapy reduced BLBC progression. Our study identified FGD5 as a positive modulator of tumor-initiating cells and suggests a potential therapeutic option for the BLBC subtype of breast cancer.
大多数基底样乳腺癌（BLBC）都是三阴性乳腺癌（TNBC），在乳腺癌亚型中，其预后最差，无远处转移生存时间最短。目前，由于缺乏可靠和有效的分子靶点，BLBC 患者尚无靶向治疗方法。在这里，我们进行了基于 BLBC 组织微阵列的免疫组织化学分析，结果表明 FacioGenital Dysplasia 5（FGD5）丰度与 BLBC 的不良预后相关。 FGD5 缺失降低了 BLBC 细胞的增殖、侵袭和肿瘤球形成能力。此外，在小鼠乳腺上皮细胞中遗传抑制 减少了肿瘤起始细胞的自我更新能力，从而减弱了 BLBC 的起始和进展。此外，FGD5 丰度与 BLBC 中的表皮生长因子受体（EGFR）丰度呈正相关。 FGD5 缺失通过减少 TNBC 细胞中 EGFR 的稳定性，在 2D 和 3D 培养条件下降低了 EGFR 的丰度。在机制上，FGD5 与 EGFR 结合，并干扰 ITCH E3 连接酶诱导的基底 EGFR 泛素化和降解。受损的 EGFR 降解导致 BLBC 细胞增殖，并促进侵袭特性和自我更新。为了验证 FGD5-EGFR 相互作用在调节 EGFR 稳定性中的作用，我们筛选了一种穿透细胞的 α-螺旋肽 PER3，它与 FGD5 结合以破坏相互作用。用肽 PER3 处理携带 BLBC 患者来源异种移植的小鼠，用或不用化疗破坏 FGD5-EGFR 相互作用，可降低 BLBC 的进展。我们的研究确定 FGD5 是肿瘤起始细胞的正调节剂，并为乳腺癌的 BLBC 亚型提供了一种潜在的治疗选择。
