Targeting BIG3–PHB2 interaction to overcome tamoxifen resistance in breast cancer cells

Yoshimaru, Tetsuro; Komatsu, Masato; Matsuo, Taisuke; Chen, Yi‐An; Murakami, Yoichi; Mizuguchi, Kenji; Mizohata, Eiichi; Inoue, Tsuyoshi; Akiyama, Miki; Yamaguchi, Rui; Imoto, Seiya; Miyano, Satoru; Miyoshi, Yasuo; Sasa, Mitsunori; Nakamura, Yusuke; Katagiri, Toyomasa

doi:10.1038/ncomms3443

Cited by 68 publications

(135 citation statements)

References 51 publications

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“…Previous studies have shown that BIG3 is frequently upregulated in ERα-positive breast cancers56 and here we found that the overexpression of BIG3 was significantly correlated with the poorer prognosis of patients with ERα-positive breast cancer based on the RNAseq2 data set from the Cancer Genome Atlas (Supplementary Fig. 5a, Log rank test; P <0.001).…”

Section: Resultssupporting

confidence: 64%

A-kinase anchoring protein BIG3 coordinates oestrogen signalling in breast cancer cells

Yoshimaru

Ono²,

Bando

et al. 2017

Nat Commun

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Approximately 70% of breast cancer cells express oestrogen receptor alpha (ERα). Previous studies have shown that the Brefeldin A-inhibited guanine nucleotide-exchange protein 3–prohibitin 2 (BIG3-PHB2) complex has a crucial role in these cells. However, it remains unclear how BIG3 regulates the suppressive activity of PHB2. Here we demonstrate that BIG3 functions as an A-kinase anchoring protein that binds protein kinase A (PKA) and the α isoform of the catalytic subunit of protein phosphatase 1 (PP1Cα), thereby dephosphorylating and inactivating PHB2. E2-induced PKA-mediated phosphorylation of BIG3-S305 and -S1208 serves to enhance PP1Cα activity, resulting in E2/ERα signalling activation via PHB2 inactivation due to PHB2-S39 dephosphorylation. Furthermore, an analysis of independent cohorts of ERα-positive breast cancers patients reveal that both BIG3 overexpression and PHB2-S39 dephosphorylation are strongly associated with poor prognosis. This is the first demonstration of the mechanism of E2/ERα signalling activation via the BIG3–PKA–PP1Cα tri-complex in breast cancer cells.

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Section: Resultssupporting

confidence: 64%

A-kinase anchoring protein BIG3 coordinates oestrogen signalling in breast cancer cells

Yoshimaru

Ono²,

Bando

et al. 2017

Nat Commun

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“…PHB2 is a tumor suppressor that on activation has been shown to prevent the progression of ERα positive breast cancer [72]. Because of its anti-estrogenic effects, it abrogates the signaling of nuclear as well as membrane associated ERα [73]. These data indicate that flaxseed is effective in altering the expression of genes implicated in a number of cancers.…”

Section: Discussionmentioning

confidence: 99%

Flaxseed and its components differentially affect estrogen targets in pre-neoplastic hen ovaries

Dikshit

Gao

Small

et al. 2016

The Journal of Steroid Biochemistry and Molecular Biology

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Flaxseed has been studied for decades for its health benefits that include anti-cancer, cardioprotective, anti-diabetic, anti-inflammatory properties. The biologically active components that mediate these effects are the omega-3 fatty acids and the lignan, secoisolaricirescinol diglucoside. We have previously shown that whole flaxseed supplemented diet decreases the severity and incidence of ovarian cancer while a 15% dose of flaxseed is most protective against inflammation and estrogen-induced chemical and genotoxicity. The objective of this study was to dissect the independent effects of the two flaxseed components on estrogen signaling and metabolism. Two and half year old hens were fed either a control diet, 15% whole flaxseed diet, defatted flax meal diet or 5% flax oil diet for 3 months after which the animals were sacrificed and blood and tissues were harvested. Whole flaxseed diet caused a decrease in expression of ERα. ERα target gene expression was assessed using RT2 profiler PCR array. Some targets involved in the IGF/insulin signaling pathway (IRS1, IGFBP4, IGFBP5) were downregulated by flaxseed and its components. Flaxseed diet also downregulated AKT expression. A number of targets related to NF-κB signaling were altered by flaxseed diet including a series of targets implicated in cancer. Whole flaxseed diet also affected E2 metabolism by increasing CYP1A1 expression with a corresponding increase in the onco-protective E2 metabolite, 2-methoxyestradiol. The weak anti-estrogens, enterolactone, enterodiol and 2-methoxyestradiol, might be working synergistically to generate a protective effect on the ovaries from hens on whole flaxseed diet by altering the estrogen signaling and metabolism.

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“…Cell-based assays and mouse xenograft studies showed that ERAP completely suppressed E2-dependent breast cancer cell growth in vitro and in vivo , respectively 10 . However, its inhibitory effect was only maintained for 24 h, most likely due to its high susceptibility to proteolytic degradation.…”

Section: Introductionmentioning

confidence: 99%

Stapled BIG3 helical peptide ERAP potentiates anti-tumour activity for breast cancer therapeutics

Yoshimaru

Aihara

Komatsu

et al. 2017

Sci Rep

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Estradiol (E2) and the oestrogen receptor-alpha (ERα) signalling pathway play pivotal roles in the proliferative activity of breast cancer cells. Recent findings show that the brefeldin A-inhibited guanine nucleotide-exchange protein 3-prohibitin 2 (BIG3-PHB2) complex plays a crucial role in E2/ERα signalling modulation in breast cancer cells. Moreover, specific inhibition of the BIG3-PHB2 interaction using the ERα activity-regulator synthetic peptide (ERAP: 165–177 amino acids), derived from α-helical BIG3 sequence, resulted in a significant anti-tumour effect. However, the duration of this effect was very short for viable clinical application. We developed the chemically modified ERAP using stapling methods (stapledERAP) to improve the duration of its antitumour effects. The stapledERAP specifically inhibited the BIG3-PHB2 interaction and exhibited long-lasting suppressive activity. Its intracellular localization without the membrane-permeable polyarginine sequence was possible via the formation of a stable α-helix structure by stapling. Tumour bearing-mice treated daily or weekly with stapledERAP effectively prevented the BIG3-PHB2 interaction, leading to complete regression of E2-dependent tumours in vivo. Most importantly, combination of stapledERAP with tamoxifen, fulvestrant, and everolimus caused synergistic inhibitory effects on growth of breast cancer cells. Our findings suggested that the stapled ERAP may be a promising anti-tumour drug to suppress luminal-type breast cancer growth.

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Targeting BIG3–PHB2 interaction to overcome tamoxifen resistance in breast cancer cells

Cited by 68 publications

References 51 publications

A-kinase anchoring protein BIG3 coordinates oestrogen signalling in breast cancer cells

A-kinase anchoring protein BIG3 coordinates oestrogen signalling in breast cancer cells

Flaxseed and its components differentially affect estrogen targets in pre-neoplastic hen ovaries

Stapled BIG3 helical peptide ERAP potentiates anti-tumour activity for breast cancer therapeutics

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