A high-throughput drug screen reveals means to differentiate triple-negative breast cancer

Abstract

Plasticity delineates cancer subtypes with more or less favourable outcomes. In breast cancer, the subtype triple-negative lacks expression of major differentiation markers, e.g., estrogen receptor α (ERα), and its high cellular plasticity results in greater aggressiveness and poorer prognosis than other subtypes. Whether plasticity itself represents a potential vulnerability of cancer cells is not clear. However, we show here that cancer cell plasticity can be exploited to differentiate triple-negative breast cancer (TNBC). Using a high-throughput imaging-based reporter drug screen with 9 501 compounds, we have identified three polo-like kinase 1 (PLK1) inhibitors as major inducers of ERα protein expression and downstream activity in TNBC cells. PLK1 inhibition upregulates a cell differentiation program characterized by increased DNA damage, mitotic arrest, and ultimately cell death. Furthermore, 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, the upregulation of genes upon PLK1 inhibition correlates with their expression in normal breast tissue and with better overall survival in breast cancer patients. Our results indicate that differentiation therapy based on PLK1 inhibition is a potential alternative strategy to treat TNBC.

Cancer-associated fibroblasts rewire the estrogen receptor response in luminal breast cancer, enabling estrogen independence

“…A recent drug screen found Polo-like Kinase1 (PLK1) inhibitors as inducers of ER-α levels and activity, in studies performed on TNBC monocultures. [ 45 ] However, in our drug screen the three PLK1 inhibitors included were not candidates of CAF-induced reduction of ER-α activity, but instead were highly toxic to the luminal MCF7 cells.…”

Cellular plasticity in the breast cancer ecosystem

“…Indeed, the TNBC phenotype appears in part to be encoded epigenetically, as treatment of cell cultures with histone deacetylase inhibitors will efficiently switch cells from an ER - to an ER + state by resetting any previous differentiation marks ( 13 , 14 ). Additionally, a signaling pathway emanating from polo-like kinase (PLK) 1 was recently demonstrated to also induce ER-α expression in TNBC cells ( 15 ). Intriguingly, PLK1 phosphorylation of the transcriptional repressors SUZ12 and ZNF198 enhances their proteasomal degradation, thereby causing widespread dysregulation of histone modifications ( 16 ).…”

Lights and Shadows on the Cancer Multi-Target Inhibitor Rigosertib (ON-01910.Na)

“…In summary, although there is still a tendency to use rigosertib as a Plk1 inhibitor [16,[25][26][27], the Plk1 inhibition mechanism for rigosertib is controversial, as there is strong evidence that this may not be the real mechanism and some alternative mechanisms have been described for the mitotic arrest phenotype.…”