Selective inhibition of EZH2 by ZLD1039 blocks H3K27methylation and leads to potent anti-tumor activity in breast cancer

Abstract Enhancer of zeste homolog 2 (EZH2) is a candidate oncogenic driver due to its prevalent overexpression and aberrant repression of tumor suppressor genes in diverse cancers. Therefore, blocking EZH2 enzyme activity may present a valid therapeutic strategy for the treatment of cancers with EZH2 overexpression including breast cancers. Here, we described ZLD1039 a potent, highly selective, and orally bioavailable small molecule inhibitor of EZH2, which inhibited breast tumor growth and metastasis. ZLD1039 considerably inhibited EZH2 methyltransferase activity with nanomolar potency, decreased global histone-3 lysine-27 (H3K27) methylation, and reactivated silenced tumor suppressors connected to increased survival of patients with breast cancer. Comparable to conditional silencing of EZH2, its inhibition by ZLD1039 decreased cell proliferation, cell cycle arrest, and induced apoptosis. Comparably, treatment of xenograft-bearing mice with ZLD1039 led to tumor growth regression and metastasis inhibition. These data confirmed the dependency of breast cancer progression on EZH2 activity and the usefulness of ZLD1039 as a promising treatment for breast cancer.

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The cholesterol metabolite 27-hydroxycholesterol increases the secretion of extracellular vesicles which promote breast cancer progression

Endocrinology ◽

10.1210/endocr/bqab095 ◽

2021 ◽

Author(s):

Amy E Baek ◽

Natalia Krawczynska ◽

Anasuya Das Gupta ◽

Svyatoslav Victorovich Dvoretskiy ◽

Sixian You ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Growth ◽

Cancer Cells ◽

Extracellular Vesicles ◽

Cancer Progression ◽

Myeloid Cells ◽

Breast Cancer Progression ◽

Label Free ◽

Tumor Growth And Metastasis ◽

Promote Breast Cancer

Abstract Cholesterol has been implicated in the clinical progression of breast cancer, a disease that continues to be the most commonly diagnosed cancer in women. Previous work has identified the cholesterol metabolite, 27-hydroxycholesterol (27HC), as a major mediator of the effects of cholesterol on breast tumor growth and progression. 27HC can act as an estrogen receptor (ER) modulator to promote the growth of ERα+ tumors, and a liver x receptor (LXR) ligand in myeloid immune cells to establish an immune-suppressive program. In fact, the metastatic properties of 27HC require the presence of myeloid cells, with neutrophils (PMNs) being essential for the increase in lung metastasis in murine models. In an effort to further elucidate the mechanisms by which 27HC alters breast cancer progression, we made the striking finding that 27HC promoted the secretion of extracellular vesicles (EVs), a diverse assortment of membrane bound particles that include exosomes. The resulting EVs had a size distribution that was skewed slightly larger, compared to EVs generated by treating cells with vehicle. The increase in EV secretion and size was consistent across three different subtypes: primary murine PMNs, RAW264.7 monocytic cells and 4T1 murine mammary cancer cells. Label-free analysis of 27HC-EVs indicated that they had a different metabolite composition to those from vehicle-treated cells. Importantly, 27HC-EVs from primary PMNs promoted tumor growth and metastasis in two different syngeneic models, demonstrating the potential role of 27HC induced EVs in the progression of breast cancer. EVs from PMNs were taken up by cancer cells, macrophages and PMNs, but not T cells. Since EVs did not alter proliferation of cancer cells, it is likely that their pro-tumor effects are mediated through interactions with myeloid cells. Interestingly, RNA-seq analysis of tumors from 27HC-EV treated mice do not display significantly altered transcriptomes, suggesting that the effects of 27HC-EVs occur early on in tumor establishment and growth. Future work will be required to elucidate the mechanisms by which 27HC increases EV secretion, and how these EVs promote breast cancer progression. Collectively however, our data indicate that EV secretion and content can be regulated by a cholesterol metabolite, which may have detrimental effects in terms of disease progression, important findings given the prevalence of both breast cancer and hypercholesterolemia.

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Review of: Tamoxifen and TRAIL synergistically induce apoptosis in breast cancer cells

Breast Cancer Online ◽

10.1017/s1470903108006676 ◽

2008 ◽

Vol 11 (2) ◽

Cited By ~ 1

Author(s):

Alison J. Butt

Keyword(s):

Breast Cancer ◽

Tumor Growth ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Single Agent ◽

Xenograft Model ◽

Estrogen Receptor Α ◽

Tumor Xenograft ◽

Breast Cancers ◽

Induced Apoptosis

Citation of original article:C. Lagadec, E. Adriaenssens, R. A. Toillon, V. Chopin, R. Romon, F. Van Coppenolle, H. Hondermarck, X. Le Bourhis. Oncogene advance online publication, 3 September 2007; doi:10.1038/sj.onc.1210749.Abstract of the original article:Tamoxifen (TAM), is widely used as a single agent in adjuvant treatment of breast cancer. Here, we investigated the effects of TAM in combination with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in estrogen receptor-α (ER-α)-positive and -negative breast cancer cells. We showed that cotreatment with TAM and TRAIL synergistically induced apoptosis regardless of ER-α status. By contrast, cotreatment did not affect the viability of normal breast epithelial cells. Cotreatment with TAM and TRAIL in breast cancer cells decreased the levels of antiapoptotic proteins including FLIPs and Bcl-2, and enhanced the levels of proapoptotic proteins such as FADD, caspase 8, tBid, Bax and caspase 9. Furthermore, cotreatment-induced apoptosis was efficiently reduced by FADD- or Bid-siRNA, indicating the implication of both extrinsic and intrinsic pathways in synergistic apoptosis induction. Importantly, cotreatment totally arrested tumor growth in an ER-α-negative MDA-MB-231 tumor xenograft model. The abrogation of tumor growth correlated with enhanced apoptosis in tumor tissues. Our findings raise the possibility to use TAM in combination with TRAIL for breast cancers, regardless of ER-α status.

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Anti-Angiogenic Effects of Phytochemicals on miRNA Regulating Breast Cancer Progression

Biomolecules ◽

10.3390/biom10020191 ◽

2020 ◽

Vol 10 (2) ◽

pp. 191 ◽

Cited By ~ 16

Author(s):

Elizabeth Varghese ◽

Alena Liskova ◽

Peter Kubatka ◽

Samson Mathews Samuel ◽

Dietrich Büsselberg

Keyword(s):

Breast Cancer ◽

Tumor Growth ◽

Tumor Progression ◽

Cancer Progression ◽

Tumor Angiogenesis ◽

Expression Profiles ◽

Metabolic Reprogramming ◽

Breast Cancers ◽

Oncogenic Signaling ◽

Metabolic Switch

Several phytochemicals have been identified for their role in modifying miRNA regulating tumor progression. miRNAs modulate the expression of several oncogenes and tumor suppressor genes including the genes that regulate tumor angiogenesis. Hypoxia inducible factor-1 alpha (HIF-1α) signaling is a central axis that activates oncogenic signaling and acts as a metabolic switch in endothelial cell (EC) driven tumor angiogenesis. Tumor angiogenesis driven by metabolic reprogramming of EC is crucial for tumor progression and metastasis in many different cancers, including breast cancers, and has been linked to aberrant miRNA expression profiles. In the current article, we identify different miRNAs that regulate tumor angiogenesis in the context of oncogenic signaling and metabolic reprogramming in ECs and review how selected phytochemicals could modulate miRNA levels to induce an anti-angiogenic action in breast cancer. Studies involving genistein, epigallocatechin gallate (EGCG) and resveratrol demonstrate the regulation of miRNA-21, miRNA-221/222 and miRNA-27, which are prognostic markers in triple negative breast cancers (TNBCs). Modulating the metabolic pathway is a novel strategy for controlling tumor angiogenesis and tumor growth. Cardamonin, curcumin and resveratrol exhibit their anti-angiogenic property by targeting the miRNAs that regulate EC metabolism. Here we suggest that using phytochemicals to target miRNAs, which in turn suppresses tumor angiogenesis, should have the potential to inhibit tumor growth, progression, invasion and metastasis and may be developed into an effective therapeutic strategy for the treatment of many different cancers where tumor angiogenesis plays a significant role in tumor growth and progression.

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Herbal Extract SH003 Suppresses Tumor Growth and Metastasis of MDA-MB-231 Breast Cancer Cells by Inhibiting STAT3-IL-6 Signaling

Mediators of Inflammation ◽

10.1155/2014/492173 ◽

2014 ◽

Vol 2014 ◽

pp. 1-11 ◽

Cited By ~ 18

Author(s):

Youn Kyung Choi ◽

Sung-Gook Cho ◽

Sang-Mi Woo ◽

Yee Jin Yun ◽

Sunju Park ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Growth ◽

Cancer Cells ◽

Cancer Progression ◽

Breast Cancer Cells ◽

Metastatic Breast ◽

Herbal Extract ◽

Tumor Growth And Metastasis ◽

Risk Of Cancer

Cancer inflammation promotes cancer progression, resulting in a high risk of cancer. Here, we demonstrate that our new herbal extract, SH003, suppresses both tumor growth and metastasis of MDA-MB-231 breast cancer cells via inhibiting STAT3-IL-6 signaling path. Our new herbal formula, SH003, mixed extract fromAstragalus membranaceus, Angelica gigas, andTrichosanthes kirilowiiMaximowicz, suppressed MDA-MB-231 tumor growth and lung metastasisin vivoand reduced the viability and metastatic abilities of MDA-MB-231 cellsin vitro. Furthermore, SH003 inhibited STAT3 activation, which resulted in a reduction of IL-6 production. Therefore, we conclude that SH003 suppresses highly metastatic breast cancer growth and metastasis by inhibiting STAT3-IL-6 signaling path.

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Lasofoxifene as a potential treatment for therapy-resistant ER-positive metastatic breast cancer

Breast Cancer Research ◽

10.1186/s13058-021-01431-w ◽

2021 ◽

Vol 23 (1) ◽

Author(s):

Muriel Lainé ◽

Sean W. Fanning ◽

Ya-Fang Chang ◽

Bradley Green ◽

Marianne E. Greene ◽

...

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Tumor Growth ◽

Ligand Binding ◽

Endocrine Therapy ◽

Breast Cancers ◽

Primary Tumor Growth ◽

Wild Type ◽

Tumor Growth And Metastasis ◽

Anti Tumor Activity

Abstract Background Endocrine therapy remains the mainstay of treatment for estrogen receptor-positive (ER+) breast cancer. Constitutively active mutations in the ligand binding domain of ERα render tumors resistant to endocrine agents. Breast cancers with the two most common ERα mutations, Y537S and D538G, have low sensitivity to fulvestrant inhibition, a typical second-line endocrine therapy. Lasofoxifene is a selective estrogen receptor modulator with benefits on bone health and breast cancer prevention potential. This study investigated the anti-tumor activity of lasofoxifene in breast cancer xenografts expressing Y537S and D538G ERα mutants. The combination of lasofoxifene with palbociclib, a CDK4/6 inhibitor, was also evaluated. Methods Luciferase-GFP tagged MCF7 cells bearing wild-type, Y537S, or D538G ERα were injected into the mammary ducts of NSG mice (MIND model), which were subsequently treated with lasofoxifene or fulvestrant as single agents or in combination with palbociclib. Tumor growth and metastasis were monitored with in vivo and ex vivo luminescence imaging, terminal tumor weight measurements, and histological analysis. Results As a monotherapy, lasofoxifene was more effective than fulvestrant at inhibiting primary tumor growth and reducing metastases. Adding palbociclib improved the effectiveness of both lasofoxifene and fulvestrant for tumor suppression and metastasis prevention at four distal sites (lung, liver, bone, and brain), with the combination of lasofoxifene/palbociclib being generally more potent than that of fulvestrant/palbociclib. X-ray crystallography of the ERα ligand binding domain (LBD) shows that lasofoxifene stabilizes an antagonist conformation of both wild-type and Y537S LBD. The ability of lasofoxifene to promote an antagonist conformation of Y537S, combined with its long half-life and bioavailability, likely contributes to the observed potent inhibition of primary tumor growth and metastasis of MCF7 Y537S cells. Conclusions We report for the first time the anti-tumor activity of lasofoxifene in mouse models of endocrine therapy-resistant breast cancer. The results demonstrate the potential of using lasofoxifene as an effective therapy for women with advanced or metastatic ER+ breast cancers expressing the most common constitutively active ERα mutations.

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Clinical profile and role of VEGF-c polymorphism in prognosis and management of breast cancer

International Journal of Molecular and Immuno Oncology ◽

10.18203/issn.2456-3994.intjmolimmunooncol20170053 ◽

2017 ◽

Vol 2 (1) ◽

pp. 11

Author(s):

Amulya Singh ◽

Gulab Dhar Yadav ◽

Anand Narayan Singh ◽

Shashwat Tiwari ◽

Vimal Choubey

Keyword(s):

Breast Cancer ◽

Tumor Growth ◽

Uttar Pradesh ◽

Vascular Endothelial ◽

Tumor Characteristics ◽

Breast Cancers ◽

Altered Expression ◽

Dietary History ◽

Tumor Growth And Metastasis ◽

Endothelial Growth Factor

Purpose: Angiogenesis is a necessary step in tumor growth and metastasis. Vascular endothelial growth factor (VEGF-c) is a major mediator of breast cancer angiogenesis. Therefore, we investigated the association of polymorphism in the VEGF-c gene with breast cancer risk and prognostic characteristics of the tumors in a case-control study. Experimental Design: We examined one polymorphism in the VEGF-c gene (+936C/T) in 75 breast cancer cases and 75 control from Kanpur, Uttar Pradesh, India and adjacent areas together with geographically selected controls. Results: None of the polymorphism or any haplotype was significantly associated with either breast cancers. Our study suggests that the +936C/T polymorphism is unlikely to be associated with breast cancer. We also analyzed the cases for genotypes or haplotypes that associated with tumor characteristics. The genotypes and haplotypes were not related with other tumor characteristics such as regional or distant metastasis, stage at diagnosis, or dietary history. Conclusions: Although none of the polymorphisms studied in the VEGF-c gene was found to influence susceptibility to breast cancer significantly, some of the VEGF-c genotypes and haplotypes may influence tumor growth through an altered expression of VEGF-c and tumor angiogenesis.

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INPP4B promotes PI3Kα-dependent late endosome formation and Wnt/β-catenin signaling in breast cancer

Nature Communications ◽

10.1038/s41467-021-23241-6 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Samuel J. Rodgers ◽

Lisa M. Ooms ◽

Viola M. J. Oorschot ◽

Ralf B. Schittenhelm ◽

Elizabeth V. Nguyen ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Growth ◽

Breast Cancer Cells ◽

Triple Negative ◽

Akt Signaling ◽

Late Endosome ◽

Breast Cancers ◽

Lysosomal Degradation ◽

Late Endosomes ◽

Mrna And Protein Expression

AbstractINPP4B suppresses PI3K/AKT signaling by converting PI(3,4)P2 to PI(3)P and INPP4B inactivation is common in triple-negative breast cancer. Paradoxically, INPP4B is also a reported oncogene in other cancers. How these opposing INPP4B roles relate to PI3K regulation is unclear. We report PIK3CA-mutant ER+ breast cancers exhibit increased INPP4B mRNA and protein expression and INPP4B increased the proliferation and tumor growth of PIK3CA-mutant ER+ breast cancer cells, despite suppression of AKT signaling. We used integrated proteomics, transcriptomics and imaging to demonstrate INPP4B localized to late endosomes via interaction with Rab7, which increased endosomal PI3Kα-dependent PI(3,4)P2 to PI(3)P conversion, late endosome/lysosome number and cargo trafficking, resulting in enhanced GSK3β lysosomal degradation and activation of Wnt/β-catenin signaling. Mechanistically, Wnt inhibition or depletion of the PI(3)P-effector, Hrs, reduced INPP4B-mediated cell proliferation and tumor growth. Therefore, INPP4B facilitates PI3Kα crosstalk with Wnt signaling in ER+ breast cancer via PI(3,4)P2 to PI(3)P conversion on late endosomes, suggesting these tumors may be targeted with combined PI3K and Wnt/β-catenin therapies.

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CBP/p300: Critical Co-Activators for Nuclear Steroid Hormone Receptors and Emerging Therapeutic Targets in Prostate and Breast Cancers

Cancers ◽

10.3390/cancers13122872 ◽

2021 ◽

Vol 13 (12) ◽

pp. 2872

Author(s):

Aaron R. Waddell ◽

Haojie Huang ◽

Daiqing Liao

Keyword(s):

Breast Cancer ◽

Prostate Cancer ◽

Tumor Growth ◽

Signaling Pathways ◽

Cell Cycle Progression ◽

Hormone Receptors ◽

Steroid Hormone Receptors ◽

Breast Cancers ◽

Creb Binding Protein ◽

Breast And Prostate Cancer

The CREB-binding protein (CBP) and p300 are two paralogous lysine acetyltransferases (KATs) that were discovered in the 1980s–1990s. Since their discovery, CBP/p300 have emerged as important regulatory proteins due to their ability to acetylate histone and non-histone proteins to modulate transcription. Work in the last 20 years has firmly established CBP/p300 as critical regulators for nuclear hormone signaling pathways, which drive tumor growth in several cancer types. Indeed, CBP/p300 are critical co-activators for the androgen receptor (AR) and estrogen receptor (ER) signaling in prostate and breast cancer, respectively. The AR and ER are stimulated by sex hormones and function as transcription factors to regulate genes involved in cell cycle progression, metabolism, and other cellular functions that contribute to oncogenesis. Recent structural studies of the AR/p300 and ER/p300 complexes have provided critical insights into the mechanism by which p300 interacts with and activates AR- and ER-mediated transcription. Breast and prostate cancer rank the first and forth respectively in cancer diagnoses worldwide and effective treatments are urgently needed. Recent efforts have identified specific and potent CBP/p300 inhibitors that target the acetyltransferase activity and the acetytllysine-binding bromodomain (BD) of CBP/p300. These compounds inhibit AR signaling and tumor growth in prostate cancer. CBP/p300 inhibitors may also be applicable for treating breast and other hormone-dependent cancers. Here we provide an in-depth account of the critical roles of CBP/p300 in regulating the AR and ER signaling pathways and discuss the potential of CBP/p300 inhibitors for treating prostate and breast cancer.

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