Wu Qitong, Siddharth Sumit, Verma Deepak, Parida Sheetal, Sharma Dipali
Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans Street, CRB 1, Rm 145, Baltimore, MD, 21231, USA.
Cell Commun Signal. 2025 May 26;23(1):244. doi: 10.1186/s12964-025-02233-9.
Triple negative breast cancer, an inherently aggressive disease, is further impaired by the limited therapeutic options and chemotherapy-resistance; hence, elucidating the signaling nodes underlying chemotherapy resistance is of major interest. Focusing on the differentially expressed genes in recurrent TNBC, we identified TRIM29, a ubiquitin ligase belonging to TRIM family, as a uniquely enriched protein in chemoresistant TNBC. Here, we demonstrate that chemoresistant TNBC cells are inherently aggressive, exhibiting elevated growth and migration potential compared to chemosensitive cells, and in particular, they possess higher TRIM29 expression whose expression level modulation results in altered chemosensitivity. TRIM29 overexpression reduces chemotherapy response whereas TRIM29 knockout not only increases chemosensitivity but also reduces TNBC tumor growth. Tumor-dissociated cells maintain TRIM29 knockout status as well as exhibit similar functional alterations as chemoresistant TNBC cells. Mechanistically, RNA-sequencing of parental-chemosensitive, chemoresistant-inherently overexpressing TRIM29 and chemoresistant-TRIM29 knockout TNBC cells reveals a unique set of genes (S100P, SERPINB3, SERPINB4, CEACAM5, CEACAM6 and CDH6) showing significant upregulation with the acquisition of chemoresistance and downregulation with the TRIM29 knockout. Furthermore, an enrichment of β-catenin pathway in chemoresistant TNBC cells is observed. We uncovered a functional network where S100P, a metastasis inducing secretory factor, bidirectionally interacts with TRIM29, and modulates the expression of SERPINB3, SERPINB4, CEACAM5, CEACAM6 as well as β-catenin pathway genes. Showing the functional importance, S100P inhibitor reduces the growth and mammosphere formation in chemoresistant TNBC. Moreover, combining β-catenin inhibitor with chemotherapy shows synergistic inhibition of chemoresistant TNBC cells. Indeed, higher expression of TRIM29, S100P and β-catenin associates with reduced recurrence free survival. This work proposes TRIM29 as an important node that modulates a unique gene network in chemoresistant TNBC and whose biological impact is mediated by modulation of S100P and β-catenin.
三阴性乳腺癌是一种本质上具有侵袭性的疾病，有限的治疗选择和化疗耐药性使其病情进一步恶化；因此，阐明化疗耐药背后的信号节点备受关注。聚焦于复发性三阴性乳腺癌中差异表达的基因，我们鉴定出TRIM29，一种属于TRIM家族的泛素连接酶，是化疗耐药性三阴性乳腺癌中独特富集的蛋白质。在此，我们证明化疗耐药性三阴性乳腺癌细胞本质上具有侵袭性，与化疗敏感细胞相比，其生长和迁移潜能升高，特别是它们具有更高的TRIM29表达，其表达水平的调节导致化疗敏感性改变。TRIM29过表达降低化疗反应，而TRIM29基因敲除不仅增加化疗敏感性，还减少三阴性乳腺癌肿瘤生长。肿瘤解离细胞维持TRIM29基因敲除状态，并表现出与化疗耐药性三阴性乳腺癌细胞相似的功能改变。机制上，对亲本化疗敏感、固有过表达TRIM29的化疗耐药性和TRIM29基因敲除的化疗耐药性三阴性乳腺癌细胞进行RNA测序，揭示了一组独特的基因（S100P、丝氨酸蛋白酶抑制剂B3、丝氨酸蛋白酶抑制剂B4、癌胚抗原相关细胞黏附分子5、癌胚抗原相关细胞黏附分子6和CDH6），随着化疗耐药性的获得显著上调，随着TRIM29基因敲除而下调。此外，在化疗耐药性三阴性乳腺癌细胞中观察到β-连环蛋白通路的富集。我们发现了一个功能网络，其中转移诱导分泌因子S100P与TRIM29双向相互作用，并调节丝氨酸蛋白酶抑制剂B3、丝氨酸蛋白酶抑制剂B4、癌胚抗原相关细胞黏附分子5、癌胚抗原相关细胞黏附分子6以及β-连环蛋白通路基因的表达。显示出功能重要性的是，S100P抑制剂减少化疗耐药性三阴性乳腺癌的生长和乳腺球形成。此外，将β-连环蛋白抑制剂与化疗联合使用对化疗耐药性三阴性乳腺癌细胞具有协同抑制作用。事实上，TRIM29、S100P和β-连环蛋白的高表达与无复发生存率降低相关。这项工作提出TRIM29是调节化疗耐药性三阴性乳腺癌中独特基因网络的重要节点，其生物学影响由S100P和β-连环蛋白的调节介导。
