Oxytocin receptor induces mammary tumorigenesis through prolactin/p-STAT5 pathway

Li, Dan; San, Mingjun; Zhang, Jing; Yang, Anlan; Xie, Wanhua; Yang, Chong‐Ren; Lü, Xiaodan; Zhang, Yuntao; Zhao, Mingyue; Feng, Xuechao; Zheng, Yaowu

doi:10.1038/s41419-021-03849-8

Cited by 15 publications

(11 citation statements)

References 58 publications

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“…This hypothesis is supported by a mouse study using MDA-MB-231 cells, where the OTR levels were higher in metastasised tumour cells than in the corresponding primary xenograft tumour cells ( Figure 2 C) [ 27 ], as well as by this study’s transwell migration assays, where selected and amplified migrated T2 and T4 cells had ~2.1-fold and ~2.5-fold higher OTR expression than the parental control cells cultured in normal medium with 10% FBS ( Figure 2 B). These results align well with recent findings in a transgenic mouse model of OTR overexpression where OTR overexpression in the tumour microenvironment promotes mammary-specific tumour growth and metastasis [ 57 ]. Patients with metastatic TNBC usually have short progression-free survival (median 3–4 months) after the failure of first-line chemotherapy [ 58 ].…”

Section: Discussionsupporting

confidence: 91%

High Oxytocin Receptor Expression Linked to Increased Cell Migration and Reduced Survival in Patients with Triple-Negative Breast Cancer

Liu

Muttenthaler

2022

Biomedicines

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Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with limited treatment options and high mortality. The oxytocin receptor (OTR) is a class-A G protein-coupled receptor that has been linked to breast cancer, but its role in tumorigenesis and disease progression remains underexplored. OTR expression is highest in tumour-adjacent breast tissue, followed by normal and tumour tissue, indicating a potential role in the tumour microenvironment. OTR levels were higher in migrated MDA-MB-231 cells than in the control parental cells cultured in normal medium; OTR overexpression/knock-down and metastasis biomarker experiments revealed that high OTR expression enhanced metastasis capabilities. These findings align well with data from a murine breast cancer metastasis model, where metastasised tumours had higher OTR expression than the corresponding primary tumours, and high OTR expression also correlates to reduced survival in TNBC patients. OTR agonists/antagonists did not affect MDA-MB-231 cell migration, and pharmacological analysis revealed that the OT/OTR signalling was compromised. High OTR expression enhanced cell migration in an OTR ligand-independent manner, with the underlying mechanism linked to the EGF-mediated ERK1/2-RSK-rpS6 pathway. Taken together, high OTR expression seems to be involved in TNBC metastasis via increasing cell sensitivity to EGF. These results support a potential prognostic biomarker role of OTR and provide new mechanistic insights and opportunities for targeted treatment options for TNBC.

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Section: Discussionsupporting

confidence: 91%

High Oxytocin Receptor Expression Linked to Increased Cell Migration and Reduced Survival in Patients with Triple-Negative Breast Cancer

Liu

Muttenthaler

2022

Biomedicines

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“…The STAT5 activation in tumor macrophages by derived factors from breast cancer cells led to the expression of anti-tumor immune stimulatory genes [50]. On the other hand, it was shown that STAT5a, an isoform of STAT5, could confer resistance to doxorubicin [51] and combined PI3K/mTOR and JAK2/STAT5 pathways inhibition induced cell death in triple-negative breast cancer [52].…”

Section: Discussionmentioning

confidence: 99%

Optimizing Therapeutic Targets for Breast Cancer Using Boolean Network Models

Sgariglia

Carneiro

Carvalho

et al. 2023

Preprint

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Since cancer is a genetic disease, studying gene regulatory networks related to this pathology offers the possibility of obtaining helpful information for therapeutic purposes. However, the complexity expressed by the interconnections between network components grows exponentially with the number of genes in the system. In this report, the Boolean logic use for regulating the existing relationships between network components has allowed us to simplify the modeling capable of producing attractors representing the cell phenotypes from breast cancer RNA-seq data. From this point of view, a therapeutic objective is to induce the cell, through appropriate interventions, to leave the current cancer attractor to migrate toward another attractor physiologically different from cancer. In this report, we developed a computational method that identifies network nodes whose inhibition achieves the therapeutic objective of transitioning from one tumor attractor to another associated with apoptosis based on transcriptomic data from cell lines. We used previously published in vitro experiments, in which the knockdown of a few proteins led a breast cancer cell line to death, to validate the model taking into account genes related to apoptosis in cancer cells. The method proposed in this manuscript uses heterogeneous data integration, structural network analysis, and biological knowledge to identify potential targets of interest for breast cancer on a personalized medicine approach.

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“…On the other hand, the down-regulation of the OXTR gene expression was reported recently in breast cancer relative to the non-cancer tissue [ 140 , 141 ]. In contrast, mammary tumorigenesis was induced by the overexpression of OXTR in a mouse model [ 142 ].…”

Section: Oxtr In Cancermentioning

confidence: 99%

Roles of the Oxytocin Receptor (OXTR) in Human Diseases

Pierzynowska

Gaffke

Żabińska

et al. 2023

IJMS

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The oxytocin receptor (OXTR), encoded by the OXTR gene, is responsible for the signal transduction after binding its ligand, oxytocin. Although this signaling is primarily involved in controlling maternal behavior, it was demonstrated that OXTR also plays a role in the development of the nervous system. Therefore, it is not a surprise that both the ligand and the receptor are involved in the modulation of behaviors, especially those related to sexual, social, and stress-induced activities. As in the case of every regulatory system, any disturbances in the structures or functions of oxytocin and OXTR may lead to the development or modulation of various diseases related to the regulated functions, which in this case include either mental problems (autism, depression, schizophrenia, obsessive-compulsive disorders) or those related to the functioning of reproductive organs (endometriosis, uterine adenomyosis, premature birth). Nevertheless, OXTR abnormalities are also connected to other diseases, including cancer, cardiac disorders, osteoporosis, and obesity. Recent reports indicated that the changes in the levels of OXTR and the formation of its aggregates may influence the course of some inherited metabolic diseases, such as mucopolysaccharidoses. In this review, the involvement of OXTR dysfunctions and OXTR polymorphisms in the development of different diseases is summarized and discussed. The analysis of published results led us to suggest that changes in OXTR expression and OXTR abundance and activity are not specific to individual diseases, but rather they influence processes (mostly related to behavioral changes) that might modulate the course of various disorders. Moreover, a possible explanation of the discrepancies in the published results of effects of the OXTR gene polymorphisms and methylation on different diseases is proposed.

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Oxytocin receptor induces mammary tumorigenesis through prolactin/p-STAT5 pathway

Cited by 15 publications

References 58 publications

High Oxytocin Receptor Expression Linked to Increased Cell Migration and Reduced Survival in Patients with Triple-Negative Breast Cancer

High Oxytocin Receptor Expression Linked to Increased Cell Migration and Reduced Survival in Patients with Triple-Negative Breast Cancer

Optimizing Therapeutic Targets for Breast Cancer Using Boolean Network Models

Roles of the Oxytocin Receptor (OXTR) in Human Diseases

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