Inhibition of UGT8 suppresses basal-like breast cancer progression by attenuating sulfatide–αVβ5 axis

Cao, Qianhua; Chen, Xingyu; Wu, Xuebiao; Liao, Ruocen; Huang, Panpan; Tan, Yanjia; Wang, Li; Ren, Guoping; Huang, Jian; Dong, Chenfang

doi:10.1084/jem.20172048

Cited by 54 publications

(37 citation statements)

References 54 publications

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“…Because only adenocarcinoma tumors exhibited both high FA2H and UGT8, this suggests that combined FA2H and UGT8 expression could drive increased 2-hydroxyHexCer levels in adenocarcinomas. Our results strongly argue that a combination of FA2H and UGT8 expression drives the synthesis of 2-hydroxyHexCer, the exact mechanism accounting for the accumulation of these metabolites specifically in adenocarcinomas, which should be confirmed by ulterior investigations of sulfatides and gangliosides, which were also linked with cancer metastasis (35,36) and multi-drug resistance (37). Aligning with the theory that complex metabolic alterations, rather than single molecule levels, should be taken into account for delineating mechanisms of disease, low FA2H was associated with tumor growth and patient survival in gastric tumors (38), but UGT8 is not overexpressed in gastric tumors in Fig.…”

Section: Discussionsupporting

confidence: 61%

High FA2H and UGT8 transcript levels predict hydroxylated hexosylceramide accumulation in lung adenocarcinoma

Lemay

Courtemanche

Couttas

et al. 2019

Journal of Lipid Research

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Supplementary key words 2-hydroxyhexosylceramide • sphingolipid • squamous • neuroendocrine • cancer • fatty acids • gene expression • mass spectrometry • fatty acid 2-hydroxylase • uridine 5′-diphosphateglycosyltransferase 8 Lung cancer is the leading cause of cancer-related deaths worldwide, with an estimated 1.8 million deaths per year (1). The overall prognosis of lung cancer patients is poor, with an 18% survival rate after 5 years (1). Given the clinical advantage of cancer type-specific therapies, it is required to enhance our understanding of differential mechanisms underlying lung cancers. Sphingolipid alterations are increasingly associated with oncogenesis (2). Sphingolipids encompass a wide array of bioactive molecules centrally involved in the determination Abstract Lung cancer causes more deaths than any other cancer. Sphingolipids encompass metabolically interconnected species whose balance has pivotal effects on proliferation, migration, and apoptosis. In this study, we paralleled quantification of sphingolipid species with quantitative (q) PCR analyses of metabolic enzymes in order to identify dysregulated routes of sphingolipid metabolism in different subtypes of lung cancers. Lung samples were submitted to histopathological reexamination in order to confirm cancer type/subtype, which included adenocarcinoma histological subtypes and squamous cell and neuroendocrine carcinomas. Compared with benign lesions and tumor-free parenchyma, all cancers featured decreased sphingosine-1-phosphate and SMs. qPCR analyses evidenced differential mechanisms leading to these alterations between cancer types, with neuroendocrine carcinomas upregulating SGPL1, but CERT1 being downregulated in adenocarcinomas and squamous cell carcinomas. 2-Hydroxyhexosylceramides (2-hydroxyHexCers) were specifically increased in adenocarcinomas. While UDPglycosyltransferase 8 (UGT8) transcript levels were increased in all cancer subtypes, fatty acid 2-hydroxylase (FA2H) levels were higher in adenocarcinomas than in squamous and neuroendocrine carcinomas. As a whole, we report differing mechanisms through which all forms of lung cancer achieve low SM and lysosphingolipids. Our results also demonstrate that FA2H upregulation is required for the accumulation of This study was funded using peer-reviewed grants from the Cancer Research Society (Grant 22339) (70%) and from the Faculty of Medicine of Université Laval using funds from a donation by Merck Sharpe and Dohme (30%). The latter company did not have any involvement in any step of this project.

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Section: Discussionsupporting

confidence: 61%

High FA2H and UGT8 transcript levels predict hydroxylated hexosylceramide accumulation in lung adenocarcinoma

Lemay

Courtemanche

Couttas

et al. 2019

Journal of Lipid Research

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“…34). In particular, sulfatide blockage decreases breast cancer cell migration and metastasis through different mechanisms, highlighting leptin binding (38) or integrin alpha V regulation (39). Based on motility assays data after sulfatide blockage, our working hypothesis (Fig.…”

Section: Discussionmentioning

confidence: 80%

Intracellular Delivery of an Antibody Targeting Gasdermin-B Reduces HER2 Breast Cancer Aggressiveness

Molina-Crespo

Cadete

Sarrió

et al. 2019

Clinical Cancer Research

136

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Purpose: Gasdermin B (GSDMB) overexpression/amplification occurs in about 60% of HER2 breast cancers, where it promotes cell migration, resistance to anti-HER2 therapies, and poor clinical outcome. Thus, we tackle GSDMB cytoplasmic overexpression as a new therapeutic target in HER2 breast cancers. Experimental Design: We have developed a new targeted nanomedicine based on hyaluronic acid-biocompatible nanocapsules, which allow the intracellular delivery of a specific anti-GSDMB antibody into HER2 breast cancer cells both in vitro and in vivo. Results: Using different models of HER2 breast cancer cells, we show that anti-GSDMB antibody loaded to nanocapsules has significant and specific effects on GSDMBoverexpressing cancer cells' behavior in ways such as (i) lowering the in vitro cell migration induced by GSDMB; (ii) enhancing the sensitivity to trastuzumab; (iii) reducing tumor growth by increasing apoptotic rate in orthotopic breast cancer xenografts; and (iv) diminishing lung metastasis in MDA-MB-231-HER2 cells in vivo. Moreover, at a mechanistic level, we have shown that AbGB increases GSDMB binding to sulfatides and consequently decreases migratory cell behavior and may upregulate the potential intrinsic procell death activity of GSDMB. Conclusions: Our findings portray the first evidence of the effectiveness and specificity of an antibody-based nanomedicine that targets an intracellular oncoprotein. We have proved that intracellular-delivered anti-GSDMB reduces diverse protumor GSDMB functions (migration, metastasis, and resistance to therapy) in an efficient and specific way, thus providing a new targeted therapeutic strategy in aggressive HER2 cancers with poor prognosis.

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“…First, bisphosphonates inhibit the growth of neoplastic cells in vitro. (17,18) Third, observational studies have reported that oral bisphosphonate use is associated with fewer first breast cancers (19)(20)(21) ; reduced risk of contralateral breast cancer (OR = 0.4) (22) ; reduced risk of a combined endpoint of recurrence, second primary breast cancer, and breast cancer mortality (23) ; and reduced risk of skeletal metastases in early breast cancer. (16) Second, preclinical studies show antitumor effects of bisphosphonates in animals, reducing tumor burden in bone and in non-osseous tissues.…”

Section: Discussionmentioning

confidence: 99%

“…(16) Second, preclinical studies show antitumor effects of bisphosphonates in animals, reducing tumor burden in bone and in non-osseous tissues. (17,18) Third, observational studies have reported that oral bisphosphonate use is associated with fewer first breast cancers (19)(20)(21) ; reduced risk of contralateral breast cancer (OR = 0.4) (22) ; reduced risk of a combined endpoint of recurrence, second primary breast cancer, and breast cancer mortality (23) ; and reduced risk of skeletal metastases in early breast cancer. (24) The UK General Practice Database showed reduced risk of all cancers, and of breast and colorectal cancers specifically, in bisphosphonate users, (25) and a nationwide Danish database suggested protection against colon cancer with alendronate use.…”

Section: Discussionmentioning

confidence: 99%

Effects of Zoledronate on Cancer, Cardiac Events, and Mortality in Osteopenic Older Women

Reid

Horne

Mihov

et al. 2019

Journal of Bone and Mineral Research

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We recently showed that zoledronate prevented fractures in older women with osteopenia (hip T-scores between −1.0 and −2.5). In addition to fewer fractures, this study also suggested that women randomized to zoledronate had fewer vascular events, a lower incidence of cancer, and a trend to lower mortality. The present analysis provides a more detailed presentation of the adverse event data from that study, a 6-year, double-blind trial of 2000 women aged >65 years recruited using electoral rolls. They were randomly assigned to receive four infusions of either zoledronate 5 mg or normal saline at 18-month intervals. Supplements of vitamin D, but not calcium, were provided. There were 1017 serious adverse events in 443 participants in the placebo group, and 820 events in 400 participants in those randomized to zoledronate (relative risk = 0.90; 95% CI, 0.81 to 1.00). These events included fractures resulting in hospital admission. Myocardial infarction occurred in 39 women (43 events) in the placebo group and in 24 women (25 events) in the zoledronate group (hazard ratio 0.60 [95% CI, 0.36 to 1.00]; rate ratio 0.58 [95% CI, 0.35 to 0.94]). For a prespecified composite cardiovascular endpoint (sudden death, myocardial infarction, coronary artery revascularization, or stroke) 69 women had 98 events in the placebo group, and 53 women had 71 events in the zoledronate group (hazard ratio 0.76 [95% CI, 0.53 to 1.08]; rate ratio 0.72 [95% CI, 0.53 to 0.98]). Total cancers were significantly reduced with zoledronate (hazard ratio 0.67 [95% CI, 0.51 to 0.89]; rate ratio 0.68 [95% CI, 0.52 to 0.89]), and this was significant for both breast cancers and for non-breast cancers. Eleven women had recurrent or second breast cancers during the study, all in the placebo group. The hazard ratio for death was 0.65 (95% CI, 0.40 to 1.06; p = 0.08), and 0.51 (95% CI, 0.30 to 0.87) in those without incident fragility fracture. These apparent beneficial effects justify further appropriately powered trials of zoledronate with these nonskeletal conditions as primary endpoints.

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Inhibition of UGT8 suppresses basal-like breast cancer progression by attenuating sulfatide–αVβ5 axis

Abstract: Cao et al. show that UGT8 promotes BLBC progression through activating sulfatide–αVβ5 axis. ZA is identified as a direct inhibitor of UGT8 and suppresses BLBC progression, suggesting that inhibition of UGT8 offers a promising opportunity for treating BLBC.

Cited by 54 publications

References 54 publications

High FA2H and UGT8 transcript levels predict hydroxylated hexosylceramide accumulation in lung adenocarcinoma

High FA2H and UGT8 transcript levels predict hydroxylated hexosylceramide accumulation in lung adenocarcinoma

Intracellular Delivery of an Antibody Targeting Gasdermin-B Reduces HER2 Breast Cancer Aggressiveness

Effects of Zoledronate on Cancer, Cardiac Events, and Mortality in Osteopenic Older Women

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