GPER signalling in both cancer-associated fibroblasts and breast cancer cells mediates a feedforward IL1β/IL1R1 response

Marco, Paola De; Lappano, Rosamaria; Francesco, Ernestina Marianna De; Cirillo, Francesca; Pupo, Marco; Avino, Silvia; Vivacqua, Adele; Abonante, Sergio; Picard, Didier; Maggiolini, Marcello

doi:10.1038/srep24354

Cited by 65 publications

(66 citation statements)

References 59 publications

(94 reference statements)

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“…142 Increased expression of IL-1R1 and consequent upregulation of IL-1 effects in fibroblasts were found to contribute to tumor aggressiveness in breast cancer. 143 Expression of IL-1R1 was increased in peripheral blood mononuclear cells of patients with schizophrenia compared to healthy controls. 144 The IL-1β-induced activation of IL-1R1 was found at the basis of pathological epileptic seizure susceptibility.…”

Section: Mutations Known In Diseasesmentioning

confidence: 97%

“…IL‐1R1 SNP rs3917267 is significantly associated with HBV infection in children, whereas SNP rs949963 was found to be associated with susceptibility to asthma . Increased expression of IL‐1R1 and consequent upregulation of IL‐1 effects in fibroblasts were found to contribute to tumor aggressiveness in breast cancer . Expression of IL‐1R1 was increased in peripheral blood mononuclear cells of patients with schizophrenia compared to healthy controls .…”

Section: Focus On the Il‐1r Familymentioning

confidence: 99%

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The family of the interleukin‐1 receptors

Boraschi

Italiani

Weil

et al. 2017

Immunological Reviews

259

225

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The extracellular forms of the IL-1 cytokines are active through binding to specific receptors on the surface of target cells. IL-1 ligands bind to the extracellular portion of their ligand-binding receptor chain. For signaling to take place, a non-binding accessory chain is recruited into a heterotrimeric complex. The intracellular approximation of the Toll-IL-1-receptor (TIR) domains of the 2 receptor chains is the event that initiates signaling. The family of IL-1 receptors (IL-1R) includes 10 structurally related members, and the distantly related soluble protein IL-18BP that acts as inhibitor of the cytokine IL-18. Over the years the receptors of the IL-1 family have been known with many different names, with significant confusion. Thus, we will use here a recently proposed unifying nomenclature. The family includes several ligand-binding chains (IL-1R1, IL-1R2, IL-1R4, IL-1R5, and IL-1R6), 2 types of accessory chains (IL-1R3, IL-1R7), molecules that act as inhibitors of signaling (IL-1R2, IL-1R8, IL-18BP), and 2 orphan receptors (IL-1R9, IL-1R10). In this review, we will examine how the receptors of the IL-1 family regulate the inflammatory and anti-inflammatory functions of the IL-1 cytokines and are, more at large, involved in modulating defensive and pathological innate immunity and inflammation. Regulation of the IL-1/IL-1R system in the brain will be also described, as an example of the peculiarities of organ-specific modulation of inflammation.

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Section: Mutations Known In Diseasesmentioning

confidence: 97%

Section: Focus On the Il‐1r Familymentioning

confidence: 99%

The family of the interleukin‐1 receptors

Boraschi

Italiani

Weil

et al. 2017

Immunological Reviews

259

225

View full text Add to dashboard Cite

show abstract

“…19 Due to its high expression in the tumor stroma, numerous studies have used FAP as a marker of activated cancer-associated fibroblasts. 14,[63][64][65] This has resulted in the widespread use of FAP as an identifier of potential CAF populations, typically in combination with negative epithelial markers such as epithelial cell adhesion molecule (EPCAM). FAP is also widely considered one of the most viable CAF-markers for potential clinical application.…”

Section: Fapmentioning

confidence: 99%

In search of definitions: Cancer‐associated fibroblasts and their markers

Nurmik

Ullmann

Rodriguez

et al. 2019

Intl Journal of Cancer

461

428

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The tumor microenvironment has been identified as one of the driving factors of tumor progression and invasion. Inside this microenvironment, cancer‐associated fibroblasts (CAFs), a type of perpetually activated fibroblasts, have been implicated to have a strong tumor‐modulating effect and play a key role in areas such as drug resistance. Identification of CAFs has typically been carried based on the expression of various “CAF markers”, such as fibroblast activation protein alpha (FAP) and alpha smooth muscle actin (αSMA), which separates them from the larger pool of fibroblasts present in the body. However, as outlined in this Review, the expression of various commonly used fibroblast markers is extremely heterogeneous and varies strongly between different CAF subpopulations. As such, novel selection methods based on cellular function, as well as further characterizing research, are vital for the standardization of CAF identification in order to improve the cross‐applicability of different research studies in the field. The aim of this review is to give a thorough overview of the commonly used fibroblast markers in the field and their various strengths and, more importantly, their weaknesses, as well as to highlight potential future avenues for CAF identification and targeting.

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“…www.nature.com/scientificreports www.nature.com/scientificreports/ Estradiol induces MCF-10A cells pyroptosis. IL-1β is secreted by fibroblasts expressing GPER via E2 30,31 . Therefore, we next examined whether MCF-10A cells exposed to E2 secreted IL-1β into the medium (Fig.…”

Section: Estradiol Promotes Mmp-3 Secretion By Mcf-10a Cells and Basmentioning

confidence: 99%

Estradiol/GPER affects the integrity of mammary duct-like structures in vitro

Deng

Miki

Nakanishi

2020

Sci Rep

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High estrogen concentration leads to an inflammatory reaction in the mammary gland tissue in vivo;however, the detailed mechanism underlying its specific effects on the breast duct has not been fully clarified. We used 3D-cultured MCF-10A acini as a breast duct model and demonstrated various deleterious effects of 17-β estradiol (E2), including the destruction of the basement membrane surrounding the acini, abnormal adhesion between cells, and cell death via apoptosis and pyroptosis. Moreover, we clarified the mechanism underlying these phenomena: E2 binds to GPER in MCF-10A cells and stimulates matrix metalloproteinase 3 (MMP-3) and interleukin-1β (IL-1β) secretion via JNK and p38 MAPK signaling pathways. IL-1β activates the IL-1R1 signaling pathway and induces continuous MMP-3 and IL-1β secretion. Collectively, our novel findings reveal an important molecular mechanism underlying the effects of E2 on the integrity of duct-like structures in vitro. Thus, E2 may act as a trigger for ductal carcinoma transition in situ.Estrogens are female hormones secreted mainly by ovaries. They serve diverse functions in the female reproductive organs (e.g., uterus and mammary gland) as well as bones, blood vessels, nerves, and brain 1-4 . Estrogens comprise three types: estrone (E1), 17-β estradiol (E2), and estriol (E3) 5 . E2 binds to estrogen receptors α and β, and the complex formed migrates to DNA of the target gene to activate its transcription 6 . In addition to these classic transcriptional mechanisms, G-protein-coupled receptor 30 (GPER) is an estrogen receptor involved in nongenomic mechanisms 7,8 . GPER expression is tissue-specific, with high expression found in the reproductive system, heart, intestine, ovary, CNS, pancreatic islets, adipose tissue, and neurons. And abnormal GPER expression is associated with depression, hypertension, diabetes, and osteoporosis 9-11 . Also, high GPER expression in breast cancer is associated with increased recurrence 12,13 . Estrogen action via GPER leads to enhanced fibronectin matrix assembly in breast cancer cells 14 . An important biological consequence of GPER activation is the regulation of cell growth and apoptotic cell death 15,16 . In this process, E2 binding to GPER causes G-protein complex dissociation 17,18 , and then the βγ subunit activates the tyrosine kinase Src, which leads to the activation of MAPK pathway 17,18 . GPER activation further activates the downstream signaling molecules such as MAPK and PI3K/ AKT 19,20 .In this study, 3D cultured MCF-10A acini were exposed to E2, which led to the disruption of basement membrane and cell death of some ductal cells. And we further revealed the underlying mechanism in which E2 binding to GPER resulted in cAMP-mediated activation of c-jun N-terminal kinase (JNK) and p38 MAPK signaling pathway, followed by interleukin 1β (IL-1β) and matrix metalloproteinase-3 (MMP-3) expression and secretion. Results Estradiol induces basement membrane disruption in MCF-10A acini.We constructed a 3D model using the immortalized non-transfo...

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GPER signalling in both cancer-associated fibroblasts and breast cancer cells mediates a feedforward IL1β/IL1R1 response

Cited by 65 publications

References 59 publications

The family of the interleukin‐1 receptors

The family of the interleukin‐1 receptors

In search of definitions: Cancer‐associated fibroblasts and their markers

Estradiol/GPER affects the integrity of mammary duct-like structures in vitro

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