There are currently no approved targeted treatments for quadruple-negative breast cancer [QNBC; ER−/PR−/HER2−/androgen receptor (AR)−], a subtype of triple-negative breast cancer (TNBC). AR-low TNBC is more proliferative and clinically aggressive than AR-high TNBC. Centrosome amplification (CA), a cancer hallmark, is rampant in TNBC, where it induces spindle multipolarity-mediated cell death unless centrosome clustering pathways are co-upregulated to avert these sequelae. We recently showed that genes that confer CA and centrosome clustering are strongly overexpressed in AR-low TNBCs relative to AR-high TNBCs. However, the molecular mechanisms that index centrosome clustering to the levels of CA are undefined. We argue that FOXM1, a cell cycle-regulated oncogene, links the expression of genes that drive CA to the expression of genes that act at kinetochores and along microtubules to facilitate centrosome clustering. We provide compelling evidence that upregulation of the FOXM1-E2F1-ATAD2 oncogene triad in AR-low TNBC is accompanied by CA and the co-upregulation of centrosome clustering proteins such as KIFC1, AURKB, BIRC5, and CDCA8, conferring profound dysregulation of cell cycle controls. Targeting FOXM1 in AR-low TNBC may render cancer cells incapable of clustering their centrosomes and impair their ability to generate excess centrosomes. Hence, our review illuminates FOXM1 as a potential actionable target for AR-low TNBC.
目前，对于四阴性乳腺癌（QNBC；即ER−/PR−/HER2−/雄激素受体[AR]−）这一三阴性乳腺癌（TNBC）亚型，尚无获批的靶向治疗方案。AR低表达型TNBC相较于AR高表达型TNBC具有更强的增殖能力和临床侵袭性。中心体扩增（CA）作为癌症的标志性特征，在TNBC中广泛存在，其会诱导纺锤体多极介导的细胞死亡，除非中心体聚集通路被共同上调以避免这些后续效应。我们近期研究发现，与AR高表达型TNBC相比，赋予CA和中心体聚集能力的基因在AR低表达型TNBC中显著过表达。然而，将中心体聚集与CA水平关联起来的分子机制尚未明确。我们认为，细胞周期调控的致癌基因FOXM1将驱动CA的基因表达与在动粒和微管上发挥作用以促进中心体聚集的基因表达联系起来。我们提供了有力证据表明，在AR低表达型TNBC中，FOXM1-E2F1-ATAD2致癌基因三联体的上调伴随着CA以及KIFC1、AURKB、BIRC5和CDCA8等中心体聚集蛋白的共同上调，从而导致细胞周期调控严重失调。靶向AR低表达型TNBC中的FOXM1可能使癌细胞无法聚集其中心体，并削弱其产生过量中心体的能力。因此，本综述揭示了FOXM1作为AR低表达型TNBC潜在可行治疗靶点的可能性。
肿瘤(癌症)患者之家