MPA/DMBA-driven mammary carcinomas

Buqué, Aitziber; Pérez-Lanzón, María; Petroni, Giulia; Humeau, Juliette; Bloy, Norma; Yamazaki, Takahiro; Sato, Ai; Kroemer, Guido; Galluzzi, Lorenzo

doi:10.1016/bs.mcb.2020.08.003

Cited by 5 publications

(7 citation statements)

References 72 publications

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“…6B) ( 23 ). The combined application of DMBA/MPA leads to the spontaneous development of aggressive mammary tumors that closely resemble many aspects of human luminal B type breast cancer, including resistance to immunotherapy ( 24 ). Cmas ΔK14 mice, lacking sialylation in the mammary gland epithelium, exhibited a remarkable improvement in tumor-free survival (TFS) with a hazard ratio (HR) of 0.234 (95% CI: 0.103 to 0.530), time-to-death (TTD, HR of 0.126 and 95% CI: 0.0428 to 0.373), and overall survival (OS, HR of 0.085 and CI95%: 0.028 to 0.260) (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Tumor sialylation controls effective anti-cancer immunity in breast cancer

Mereiter,

Jonsson,

Oliveira

et al. 2023

Preprint

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Immunotherapies have revolutionized treatment and management of cancers. However, the use of immune checkpoint inhibitors (ICIs) in breast cancer is limited due to lack of efficacy. Sialylation, the modification of glycans with sialic acid, is frequently upregulated in various cancer types and has potent immunoregulatory properties. However, its specific role in breast cancer immune evasion has remained largely elusive. Here, we show that breast cancer sialylation drives the recruitment of polymorphonuclear myeloid suppressor cells to the tumor microenvironment, thus hampering the efficient eradication of tumors by CD8+ T cells. Notably, abrogation of tumor sialylation, either genetically or pharmacologically, not only facilitated CD8-mediated tumor control but also enabled the recruitment of Tcf7+ memory T cells. Significantly, abrogation of sialylation sensitized PD-1-resistant breast tumors to immunotherapy. Sialylation interference was well-tolerated in mammary development and function. We further demonstrate that hyper-sialylation occurs in over half of human breast cancers and correlates with poor T cell infiltration. Our results establish sialylation as a central immunoregulator in breast cancer, orchestrating multiple pathways that ultimately culminate in immune evasion. Importantly, our study underscores the potential of targeting this pathway to enhance tumor control, converting immunologically inert tumors into inflamed ones, and prime tumors for synergistic interventions involving immune checkpoint inhibitors.

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Section: Resultsmentioning

confidence: 99%

“…6B) (23). The combined application of DMBA/MPA leads to the spontaneous development of aggressive mammary tumors that closely resemble many aspects of human luminal B breast cancer, including resistance to immunotherapy (24).…”

Section: Sialylation Deficiency Increases Cancer Immunosurveillance I...mentioning

confidence: 99%

Tumor sialylation controls effective anti-cancer immunity in breast cancer

Mereiter,

Jonsson,

Oliveira

et al. 2023

Preprint

Self Cite

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“…DMBA requires metabolic activation by cytochrome P450 enzymes to generate a DNA-reactive metabolite that forms DNA adducts and induces mutations and chromosomal aberrations. DMBA can also activate oncogenic signaling pathways, such as the aryl hydrocarbon receptor (AhR), the Wnt pathway, the NF-κB pathway, and the prolyl isomerase Pin-1, which can promote cell proliferation, survival, and invasion [ 39 ]. DMBA can induce different types of breast or skin tumors in mice, depending on the dose, route of administration, genetic background, and hormonal status of the animals [ 40 ].…”

Section: Examples Of Chemical Carcinogens In Mouse Cancer Modelsmentioning

confidence: 99%

Relevance of Carcinogen-Induced Preclinical Cancer Models

Sewduth,

Georgelou

2024

JoX

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Chemical agents can cause cancer in animals by damaging their DNA, mutating their genes, and modifying their epigenetic signatures. Carcinogen-induced preclinical cancer models are useful for understanding carcinogen-induced human cancers, as they can reproduce the diversity and complexity of tumor types, as well as the interactions with the host environment. However, these models also have some drawbacks that limit their applicability and validity. For instance, some chemicals may be more effective or toxic in animals than in humans, and the tumors may differ in their genetics and phenotypes. Some chemicals may also affect normal cells and tissues, such as by causing oxidative stress, inflammation, and cell death, which may alter the tumor behavior and response to therapy. Furthermore, some chemicals may have variable effects depending on the exposure conditions, such as dose, route, and duration, as well as the animal characteristics, such as genetics and hormones. Therefore, these models should be carefully chosen, validated, and standardized, and the results should be cautiously interpreted and compared with other models. This review covers the main features of chemically induced cancer models, such as genetic and epigenetic changes, tumor environment, angiogenesis, invasion and metastasis, and immune response. We also address the pros and cons of these models and the current and future challenges for their improvement. This review offers a comprehensive overview of the state of the art of carcinogen-induced cancer models and provides new perspectives for cancer research.

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“…In the latest study of 2021, An individual PAH 7,12-dimethylbenzene[ a ]anthracene (DMBA) was orally administered to wild-type female mice treated with subcutaneous sustained-release medroxyprogesterone (MPA) pellets. Breast cancer subsequently developed and many of its associated immunobiological features appeared, including immune surveillance evasion, infrequent immune infiltration, and immunosuppression, as well as great resistance to immune checkpoint blockers targeting PD-1 [ 117 ]. It was previously demonstrated that DMBA-driven mammary carcinomas in mice displayed features similar to human hormone receptor (HR + ) breast cancer (HR + BC) cells: enrichment with activating PIK3CA mutations and loss of PTEN [ 118 ].…”

Section: How Pahs Influence the Human Bodymentioning

confidence: 99%

“…Mouse HR + BC cell lines have showed their abilities to evade immune surveillance in their hosts of origin, indicating their limited antigenic or adjuvant properties to the immune system [ 119 , 120 ]. Similarly, this MPA/DMBA-driven mammary carcinomas also displayed similar histological and transcriptional features to human HR + BC, which emerges by evading lymphoid immune surveillance, is scarcely infiltrated by immune cells, and displays markers of local immunosuppression [ 117 ].…”

Section: How Pahs Influence the Human Bodymentioning

confidence: 99%

Effect of polycyclic aromatic hydrocarbons on immunity

Jin

2022

Journal of Translational Autoimmunity

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MPA/DMBA-driven mammary carcinomas

Cited by 5 publications

References 72 publications

Tumor sialylation controls effective anti-cancer immunity in breast cancer

Tumor sialylation controls effective anti-cancer immunity in breast cancer

Relevance of Carcinogen-Induced Preclinical Cancer Models

Effect of polycyclic aromatic hydrocarbons on immunity

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