PDF(Pubmed)
Abstract：
African American (AA) women are twice as likely to develop triple-negative breast cancer (TNBC) as women of European descent. Additionally, AA women with TNBC present a much more aggressive disease course than their European American (EA) counterparts. Thus, there is an unmet clinical need to identify race-specific biomarkers and improve survival outcomes in AA patients with TNBC. The minus-end directed microtubule motor protein kinesin family member C1 (KIFC1) promotes centrosome clustering and chromosomal instability and is often overexpressed in TNBC. Previous findings suggest that KIFC1 plays a role in cell proliferation and migration in TNBC cells from AAs and that the levels of nuclear KIFC1 (nKIFC1) are particularly high in AA patients with TNBC. The nuclear localization of KIFC1 in interphase may underlie its previously unrecognized race-specific association. In this study, we found that in TNBC cells derived from AAs, nKIFC1 interacted with the tumor suppressor myosin heavy chain 9 (MYH9) over EA cells. Treatment of AA TNBC cells with commercial inhibitors of KIFC1 and MYH9 disrupted the interaction between KIFC1 and MYH9. To characterize the racial differences in the KIFC1-MYH9-MYC axis in TNBC, we established homozygous KIFC1 knockout (KO) TNBC cell lines. KIFC1 KO significantly inhibited proliferation, migration, and invasion in AA TNBC cells but not in EA TNBC cells. RNA sequencing analysis showed significant downregulation of genes involved in cell migration, invasion, and metastasis upon KIFC1 KO in TNBC cell lines from AAs compared to those from EAs. These data indicate that mechanistically, the role of nKIFC1 in driving TNBC progression and metastasis is stronger in AA patients than in EA patients, and that KIFC1 may be a critical therapeutic target for AA patients with TNBC.
摘要：
非洲裔美国人（AA）女性患三阴性乳腺癌（TNBC）的可能性是欧洲裔女性的两倍。此外,患有TNBC的AA女性比欧美（EA）女性的疾病病程更具侵略性。因此，在患有TNBC的AA患者中,鉴定种族特异性生物标志物和改善生存结局的临床需求尚未得到满足.负端定向微管运动蛋白驱动蛋白家族成员C1（KIFC1）促进中心体聚集和染色体不稳定性，并且通常在TNBC中过表达。先前的发现表明，KIFC1在来自AA的TNBC细胞中的细胞增殖和迁移中起作用，并且在患有TNBC的AA患者中，核KIFC1（nKIFC1）的水平特别高。KIFC1在间期的核定位可能是其先前未被识别的种族特异性关联的基础。在这项研究中,我们发现在来自AAs的TNBC细胞中，nKIFC1在EA细胞上与肿瘤抑制肌球蛋白重链9(MYH9)相互作用。用KIFC1和MYH9的商业抑制剂处理AATNBC细胞破坏了KIFC1和MYH9之间的相互作用。为了表征TNBC中KIFC1-MYH9-MYC轴的种族差异，我们建立了纯合KIFC1敲除（KO）TNBC细胞系。KIFC1KO显著抑制增殖，迁移,在AATNBC细胞中和侵袭，但在EATNBC细胞中没有。RNA测序分析表明，参与细胞迁移的基因显著下调，入侵,与来自EA的TNBC细胞系相比，来自AA的KIFC1KO的转移。这些数据表明，从机制上讲，AA患者中nKIFC1在驱动TNBC进展和转移中的作用强于EA患者，KIFC1可能是AA患者TNBC的关键治疗靶点。
