Chen Jungang, Lin Zhen, Fan Jiaojiao, Monzavi-Karbassi Behjatolah, Kelly Thomas, Post Steven R, Dai Lu, Qin Zhiqiang
Department of Pathology, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences 4301 W. Markham St., Little Rock, AR 72205, USA.
Department of Pathology, Tulane University Health Sciences Center, Tulane Cancer Center 1700 Tulane Ave., New Orleans, LA 70112, USA.
Am J Cancer Res. 2024 Apr 15;14(4):1545-1560. doi: 10.62347/LYDF1241. eCollection 2024.
Breast cancer represents the leading cancer type and leading cause of cancer-related death among women in the world. Triple-negative breast cancer (TNBC) is a subset of breast cancer with the poorest prognosis and still lacking of effective therapeutic options. We recently screened a natural product library and identified 3 new hit compounds with selective and prominent anti-TNBC activities on different subtype of TNBC cell lines. Interestingly, all of these 3 hit compounds belong to "cytoskeletal drugs" that target tubulin and microtubule function. Our data also showed that these hit compounds showed consistently effective on TNBC cells which are resistant to those currently used antimicrotubule agents such as Paclitaxel. RNA-Sequencing analyses revealed the anti-TNBC mechanisms of these hit compounds and identified a subset of new cellular factors commonly affected by hit compounds in different subtypes of TNBC cells. Among them, we demonstrated AHCYL1 and SPG21 as new microtubule-associated proteins, which were required for TNBC cell survival with clinical implication through tissue array analysis. Our studies provide new insights into the mechanisms of TNBC pathogenesis and offer promising therapeutic directions for this aggressive breast cancer.
乳腺癌是全球女性中最主要的癌症类型及癌症相关死亡的主要原因。三阴性乳腺癌（TNBC）是乳腺癌的一个亚型，预后最差，且仍缺乏有效的治疗方案。我们最近筛选了一个天然产物库，并鉴定出3种新的活性化合物，它们对不同亚型的TNBC细胞系具有选择性且显著的抗TNBC活性。有趣的是，这3种活性化合物均属于靶向微管蛋白和微管功能的“细胞骨架药物”。我们的数据还表明，这些活性化合物对目前使用的抗微管药物（如紫杉醇）耐药的TNBC细胞始终有效。RNA测序分析揭示了这些活性化合物的抗TNBC机制，并鉴定出在不同亚型的TNBC细胞中受活性化合物共同影响的一组新的细胞因子。其中，我们证明AHCYL1和SPG21是新的微管相关蛋白，通过组织芯片分析表明它们是TNBC细胞存活所必需的，具有临床意义。我们的研究为TNBC发病机制提供了新的见解，并为这种侵袭性乳腺癌提供了有前景的治疗方向。
