Cancer researchDec 7, 2014

Role of PLK1 in hormone-independent growth of estrogen receptor-positive breast cancer

Circadian Biology Weekly Brief ↗PubMed ↗DOI ↗

Updated Mar 29, 2026

Abstract

Polo-like kinase 1 (PLK1) downregulation inhibited estrogen-independent activity and growth in long-term estrogen-deprived (LTED) ER α-positive breast cancer cells.

High levels of PLK1 mRNA and protein were associated with increased Ki-67 scores in primary ER(+) breast cancers following aromatase inhibitor treatment.
Knockdown of PLK1 led to decreased ER expression, estrogen-independent growth, and ER transcription in LTED breast cancer cell lines.
Inhibition of PLK1 using the drug volasertib resulted in reduced LTED cell growth, ER transcriptional activity, and ER expression.
Combining volasertib with the ER antagonist fulvestrant showed greater effectiveness in reducing MCF7 xenograft growth in ovariectomized mice than either drug alone.
JUNB levels were significantly higher in LTED cells compared to parental cells, and its knockdown also reduced ER expression and transcriptional activity.

Simplified

Estrogen receptor (ER) α-positive breast cancers initially respond to antiestrogens but eventually become estrogen independent and recur. ER(+) breast cancer cells resistant to long-term estrogen deprivation (LTED) exhibit hormone-independent ER transcriptional activity and growth. A kinome-wide siRNA screen using a library targeting 720 kinases identified Polo-like kinase 1 (PLK1) as one of the top genes whose downregulation resulted in inhibition of estrogen-independent ER transcriptional activity and growth of LTED cells. High PLK1 mRNA and protein correlated with a high Ki-67 score in primary ER(+) breast cancers after treatment with the aromatase inhibitor letrozole. RNAi-mediated knockdown of PLK1 inhibited ER expression, estrogen-independent growth, and ER transcription in MCF7 and HCC1428 LTED cells. Pharmacologic inhibition of PLK1 with volasertib, a small-molecule ATP-competitive PLK1 inhibitor, decreased LTED cell growth, ER transcriptional activity, and ER expression. Volasertib in combination with the ER antagonist, fulvestrant, decreased MCF7 xenograft growth in ovariectomized mice more potently than each drug alone. JUNB, a component of the AP-1 complex, was expressed 16-fold higher in MCF7/LTED compared with parental MCF7 cells. Furthermore, JUNB and BCL2L1 (which encodes antiapoptotic BCL-xL) mRNA levels were markedly reduced upon volasertib treatment in MCF7/LTED cells, while they were increased in parental MCF7 cells. Finally, JUNB knockdown decreased ER expression and transcriptional activity in MCF7/LTED cells, suggesting that PLK1 drives ER expression and estrogen-independent growth via JUNB. These data support a critical role of PLK1 in acquired hormone-independent growth of ER(+) human breast cancer and is therefore a promising target in tumors that have escaped estrogen deprivation therapy.

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Role of PLK1 in hormone-independent growth of estrogen receptor-positive breast cancer

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