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CUL4B renders breast cancer cells tamoxifen-resistant via miR-32-5p/ER-α36 axis

Yuxing Wang¹, Xiaohua Pan², Yanjun Li¹

¹Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, PR China.

The Journal of Pathology

|February 27, 2021

Abstract:

Tamoxifen (TAM) resistance is a significant clinical challenge in endocrine therapies for estrogen receptor (ER)-positive breast cancer patients. Cullin 4B (CUL4B), which acts as a scaffold protein in CUL4B-RING ubiquitin ligase complexes (CRL4B), is frequently overexpressed in cancer and represses tumor suppressors through diverse epigenetic mechanisms. However, the role and the underlying mechanisms of CUL4B in regulating drug resistance remain unknown. Here, we showed that CUL4B promotes TAM resistance in breast cancer cells through a miR-32-5p/ER-α36 axis. We found that upregulation of CUL4B correlated with decreased TAM sensitivity of breast cancer cells, and knockdown of CUL4B or expression of a dominant-negative CUL4B mutant restored the response to TAM in TAM-resistant MCF7-TAM^R and T47D-TAM^R cells. Mechanistically, we demonstrated that CUL4B renders breast cancer cells TAM-resistant by upregulating ER-α36 expression, which was mediated by downregulation of miR-32-5p. We further showed that CRL4B epigenetically represses the transcription of miR-32-5p by catalyzing monoubiquitination at H2AK119 and coordinating with PRC2 and HDAC complexes to promote trimethylation at H3K27 at the promoter of miR-32-5p. Pharmacologic or genetic inhibition of CRL4B/PRC2/HDAC complexes significantly increased TAM sensitivity in breast cancer cells in vitro and in vivo. Taken together, our findings thus establish a critical role for the CUL4B-miR-32-5p-ER-α36 axis in the regulation of TAM resistance and have important therapeutic implications for combined application of TAM and the inhibitors of CRL4B/PRC2/HDAC complex in breast cancer treatment. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Insights

Cullin 4B (CUL4B) promotes tamoxifen resistance in breast cancer by downregulating miR-32-5p, leading to increased ER-α36. Inhibiting CUL4B complexes restores tamoxifen sensitivity, offering new therapeutic strategies.

Area of Science:

Oncology
Molecular Biology
Epigenetics

Background:

Tamoxifen (TAM) resistance is a major obstacle in treating estrogen receptor (ER)-positive breast cancer.
Cullin 4B (CUL4B) is overexpressed in cancers and linked to tumor suppressor repression via epigenetic mechanisms.
The role of CUL4B in drug resistance, particularly TAM resistance, is not well understood.

Purpose of the Study:

To investigate the role of Cullin 4B (CUL4B) in tamoxifen (TAM) resistance in breast cancer.
To elucidate the underlying molecular mechanisms by which CUL4B influences TAM sensitivity.
To explore potential therapeutic strategies targeting the CUL4B pathway for overcoming TAM resistance.

Main Methods:

Investigated the correlation between CUL4B expression and TAM sensitivity in breast cancer cells.
Utilized knockdown and dominant-negative CUL4B mutants to assess effects on TAM response.
Examined the miR-32-5p/ER-α36 axis and CRL4B's epigenetic regulation of miR-32-5p transcription.
Assessed the impact of inhibiting CRL4B/PRC2/HDAC complexes on TAM sensitivity in vitro and in vivo.

Main Results:

CUL4B upregulation correlated with decreased TAM sensitivity in breast cancer cells.
CUL4B knockdown or inhibition restored TAM sensitivity in resistant cell lines.
CUL4B promotes TAM resistance by upregulating ER-α36 via downregulation of miR-32-5p.
CRL4B epigenetically represses miR-32-5p transcription through H2AK119 monoubiquitination and PRC2/HDAC complex coordination.
Inhibition of CRL4B/PRC2/HDAC complexes significantly enhanced TAM sensitivity.

Conclusions:

The CUL4B-miR-32-5p-ER-α36 axis is a critical regulator of tamoxifen resistance in breast cancer.
CUL4B's epigenetic repression of miR-32-5p drives TAM resistance by increasing ER-α36 expression.
Targeting CUL4B complexes offers a promising therapeutic strategy for overcoming TAM resistance in breast cancer patients.

Read full analysis

Keywords:

CUL4B ER-α36 breast cancer miR-32-5p tamoxifen resistance

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