Kinome-wide functional screen identifies role of PLK1 in hormone-independent, ER-positive breast cancer

Neil E. Bhola, Valerie M. Jansen, Sangeeta Bafna, Jennifer M. Giltnane, Justin M. Balko, Monica V. Estrada, Ingrid Meszoely, Ingrid Mayer, Vandana Abramson, Fei Ye, Melinda Sanders, Teresa C. Dugger, Eliezer V. Allen, Carlos L. Arteaga

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)405-414
Number of pages10
JournalCancer Research
Volume75
Issue number2
DOIs
StatePublished - Jan 15 2015

Fingerprint

Estrogen Receptors
Estrogens
Hormones
Breast Neoplasms
Growth
letrozole
MCF-7 Cells
polo-like kinase 1
Messenger RNA
Aromatase Inhibitors
Estrogen Receptor Modulators
Transcription Factor AP-1
RNA Interference
Heterografts
Small Interfering RNA
Growth Hormone
Libraries
Phosphotransferases
Down-Regulation
Adenosine Triphosphate

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Kinome-wide functional screen identifies role of PLK1 in hormone-independent, ER-positive breast cancer. / Bhola, Neil E.; Jansen, Valerie M.; Bafna, Sangeeta; Giltnane, Jennifer M.; Balko, Justin M.; Estrada, Monica V.; Meszoely, Ingrid; Mayer, Ingrid; Abramson, Vandana; Ye, Fei; Sanders, Melinda; Dugger, Teresa C.; Allen, Eliezer V.; Arteaga, Carlos L.

In: Cancer Research, Vol. 75, No. 2, 15.01.2015, p. 405-414.

Research output: Contribution to journalArticle

Bhola, NE, Jansen, VM, Bafna, S, Giltnane, JM, Balko, JM, Estrada, MV, Meszoely, I, Mayer, I, Abramson, V, Ye, F, Sanders, M, Dugger, TC, Allen, EV & Arteaga, CL 2015, 'Kinome-wide functional screen identifies role of PLK1 in hormone-independent, ER-positive breast cancer', Cancer Research, vol. 75, no. 2, pp. 405-414. https://doi.org/10.1158/0008-5472.CAN-14-2475
Bhola, Neil E. ; Jansen, Valerie M. ; Bafna, Sangeeta ; Giltnane, Jennifer M. ; Balko, Justin M. ; Estrada, Monica V. ; Meszoely, Ingrid ; Mayer, Ingrid ; Abramson, Vandana ; Ye, Fei ; Sanders, Melinda ; Dugger, Teresa C. ; Allen, Eliezer V. ; Arteaga, Carlos L. / Kinome-wide functional screen identifies role of PLK1 in hormone-independent, ER-positive breast cancer. In: Cancer Research. 2015 ; Vol. 75, No. 2. pp. 405-414.
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abstract = "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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AU - Bafna, Sangeeta

AU - Giltnane, Jennifer M.

AU - Balko, Justin M.

AU - Estrada, Monica V.

AU - Meszoely, Ingrid

AU - Mayer, Ingrid

AU - Abramson, Vandana

AU - Ye, Fei

AU - Sanders, Melinda

AU - Dugger, Teresa C.

AU - Allen, Eliezer V.

AU - Arteaga, Carlos L.

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