Polo-like kinase 1 inhibitors differentiate triple-negative breast cancer towards a luminal cell fate

Plasticity delineates cancer subtypes with more or less favourable outcomes. In breast cancer, triple-negative is the subtype that lacks the expression of major differentiation markers (i.e. estrogen receptor [ER]), ant its high cellular plasticity results in higher aggressiveness and poor prognosis compared to other subtypes. Whether plasticity poses a vulnerability to cancer cells remains elusive. Here, we show that cancer cell plasticity can be exploited to differentiate triple-negative breast cancer. Using a high-throughput reporter drug screen with 9,501 compounds, we identify three polo-like kinase 1 (PLK1) inhibitors as major inducers of ER protein expression and downstream activity in triple-negative breast cancer cells via the transcription factor BATF. PLK1 inhibition upregulates a cell differentiation program characterized by increased DNA damage, mitotic arrest and ultimately cell death. Notably, cells surviving PLK1 inhibition have decreased tumorigenic potential, and targeting PLK1 in already established tumours reduces tumour growth both in cell line and patient-derived xenograft models. In addition, genes upregulated upon PLK1 inhibition are correlated with expression in normal breast tissue and confer better overall survival in breast cancer patients. Our results indicate that differentiation therapy based on PLK1 inhibition might be an alternative strategy to treat triple-negative breast cancer.

细胞可塑性可区分癌症亚型，并关联不同的预后结局。在乳腺癌中，三阴性乳腺癌（triple-negative breast cancer, TNBC）亚型缺乏主要分化标志物的表达，例如雌激素受体（estrogen receptor, ER）；相较于其他乳腺癌亚型，三阴性乳腺癌具有较高的细胞可塑性，因此侵袭性更强、预后更差。细胞可塑性是否会使癌细胞产生可靶向的脆弱性，目前仍不明确。本研究证实，可利用癌细胞的可塑性实现三阴性乳腺癌的分化诱导。通过针对9501种化合物的高通量报告基因药物筛选，我们发现三种polo样激酶1（polo-like kinase 1, PLK1）抑制剂可通过转录因子BATF，在三阴性乳腺癌细胞中显著诱导雌激素受体蛋白的表达及其下游通路活性。抑制PLK1可上调细胞分化程序，该程序以DNA损伤加剧、有丝分裂阻滞，并最终导致细胞死亡为特征。值得注意的是，经PLK1抑制处理后存活的癌细胞，其致瘤能力显著降低；在已建立的肿瘤模型中，靶向PLK1可在细胞系移植瘤和患者来源的异种移植瘤（patient-derived xenograft, PDX）模型中均抑制肿瘤生长。此外，PLK1抑制后上调的基因，其表达模式与正常乳腺组织的基因表达特征一致，且与乳腺癌患者更长的总生存期相关。本研究结果表明，基于PLK1抑制的分化疗法，或可成为治疗三阴性乳腺癌的新型策略。