Knockdown of the Prolactin Receptor Inhibits Recruitment of Tregs and their Promotion of EMT in a Syngeneic Breast Cancer Model
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA436638 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6797920_1.fastq.gz | Fastqsanger.gz | |||
| SRR6797920_2.fastq.gz | Fastqsanger.gz | |||
| SRR6797921_1.fastq.gz | Fastqsanger.gz | |||
| SRR6797921_2.fastq.gz | Fastqsanger.gz | |||
| SRR6797922_1.fastq.gz | Fastqsanger.gz |
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Project description:The clinical relevance and prognostic significance of tumor-infiltrating Tregs in different types of cancers makes them appealing therapeutic targets. However, while effective at inhibiting cancer progression, immunotherapeutics targeting Treg function have adverse effects in a substantial proportion of patients, ranging from mild inflammatory disorders to frank autoimmune disease. Here, we report that systemic knockdown of the long form of the prolactin receptor (LFPRLR) inhibits recruitment of Tregs to primary tumors and, importantly, metastasis-promoting activities of tumor Tregs, with no change in the production of TGFβ or IL-10 by tumor Tregs or the ability of peripheral Tregs to suppress anti-CD3/CD28-stimulated effector cell proliferation. Knockdown of the LFPRLR was accomplished using a derivatized DNA splice-modulating oligomer and outcome was assessed in the highly-metastatic, syngeneic, orthotopic 4T1-Balb/c immune-competent breast cancer model. We conclude that knockdown of the LFPRLR produces a more functionally-specific anti-cancer effect in Tregs, suggesting promise as a future therapeutic approach.
2019-02-28 | GSE111329 | GEO
Project description:Primary hyperparathyroidism is a common endocrine disorder frequently affecting postmenopausal women. In this study we have investigated expression of the prolactin receptor (PRLr) in a panel of 37 sporadic parathyroid tumours, as well as functionality in vitro in cultured parathyroid tumour cells. High levels of the prolactin receptor gene (PRLR) transcripts were demonstrated in parathyroid tissues as compared to other reference tissues and breast cancer cells. PRLr products of 60/70 kDa were highly expressed in all parathyroid tumours. In addition varying levels of the 80 kDa PRLr isoform, with known proliferative activity, were demonstrated. In parathyroid tumours PRLr immunoreactivity was observed in cytoplasm in all cases and in addition in the plasma membrane (n = 12) or enlarged lysosomes (n = 4). In normal parathyroid rim PRLr was expressed in cytoplasm and granulae. In in vitro studies of short-term cultured human parathyroid tumour cells prolactin stimulation was associated with transcriptional changes in JAK/STAT, RIG-I like receptor and type II interferon signaling pathways as documented by gene expression profiling. Moreover, PRLR gene expression in parathyroid tumors was significantly inversely correlated with plasma total Ca2+ levels. In conclusion, the prolactin receptor was found highly abundant in human parathyroid gland, parathyroid tumours, correlated with patient Ca2+ levels and functionally responsive to physiological levels of prolactin. These findings suggest a role for the prolactin receptor in human parathyroid adenomas. Expression profiling was done in parathyroid adenomas subjected to prolactin treatment in culture. In addition, corresponding paraffin sections were obtained for verification of PRLr expression by immunohistochemistry. 200 mg/L prolactin (recombinant humanM-BM- prolactin, Cat. No. JM-4687-50, MBL Woburn, MA) was added to 1M-CM-^W 10^6 attached parathyroid tumour cells. Cells were harvested using RNAlater (QIAGEN) and homogenized with QIAshredder for RNA extraction after 3 h and 24 h in culture, respectively. Negative controls were collected in parallel with each case at the same time points. RNA was extracted using QIA Cube, and quality assessed with Bioanalyser and Nanodrop. Expression array profiling and data analysis was done at the KI core facility Bioinformatics and Expression Analysis (BEA, Novum, Huddinge) using the Affymetrix platform and the TITAN ST 1.1 array. A total of 16 samples were analysed including 4 parathyroid adenomas cultured for 3 h or 24 h in the presence of prolactin plus control samples cultured in parallel without prolactin.
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Project description:Human infants are born to breastfeed. While 50% of lactating persons report struggling to make enough milk, there are no governmentally-approved drugs to enhance lactation1. Here, we engineer a variant of the naturally-occurring driver of lactation, the hormone Prolactin, to increase its serum half-life and produce a viable drug candidate. Our engineered variant,Prolactin-eXtra Long-acting(Prolactin-XL), is comprised of endogenously active human prolactin fused to an engineered human IgG1 Fc domain designed to overcome the unique drug development challenges specific to the lactating person-infant dyad. Our Prolactin-XL has a serum half-life of 70.9h in mice, 2,625-fold longer than endogenously active prolactin alone (70.9h v. 0.027h). We demonstrate that Prolactin-XL increases milk production and restores growth of pups fed by dams with pharmacologically-ablated lactation. We show that Prolactin-XL-enhanced lactation is accompanied by reversible, alveolar cell-driven changes in mammary gland morphology. Prolactin-XL treatment was associated with no identifiable pathology or adverse side effect in the lactating mice or nursing pups. This work establishes long-acting prolactins as a potentially powerful pharmacologic means to combat insufficient lactation. Implications for future research in lactating mammary gland biology and a potential preclinical path for developing Prolactin-XL for use in lactating persons are discussed.
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Project description:Primary hyperparathyroidism is a common endocrine disorder frequently affecting postmenopausal women. In this study we have investigated expression of the prolactin receptor (PRLr) in a panel of 37 sporadic parathyroid tumours, as well as functionality in vitro in cultured parathyroid tumour cells. High levels of the prolactin receptor gene (PRLR) transcripts were demonstrated in parathyroid tissues as compared to other reference tissues and breast cancer cells. PRLr products of 60/70 kDa were highly expressed in all parathyroid tumours. In addition varying levels of the 80 kDa PRLr isoform, with known proliferative activity, were demonstrated. In parathyroid tumours PRLr immunoreactivity was observed in cytoplasm in all cases and in addition in the plasma membrane (n = 12) or enlarged lysosomes (n = 4). In normal parathyroid rim PRLr was expressed in cytoplasm and granulae. In in vitro studies of short-term cultured human parathyroid tumour cells prolactin stimulation was associated with transcriptional changes in JAK/STAT, RIG-I like receptor and type II interferon signaling pathways as documented by gene expression profiling. Moreover, PRLR gene expression in parathyroid tumors was significantly inversely correlated with plasma total Ca2+ levels. In conclusion, the prolactin receptor was found highly abundant in human parathyroid gland, parathyroid tumours, correlated with patient Ca2+ levels and functionally responsive to physiological levels of prolactin. These findings suggest a role for the prolactin receptor in human parathyroid adenomas.
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Project description:The exact role of prolactin on breast cancer still remains unclear. Clues supportive or unsurpportive for prolactin to be cancer driver are confusing. To clarify the role of autocrine prolactin of breast cancer cells on cancer development, we construct T47D cells overexpressing prolactin.
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Project description:Tumor-stromal communication within the microenvironment contributes to initiation of metastasis and may present a therapeutic opportunity. Using serial single cell RNA-sequencing in an orthotopic mouse prostate cancer model, we find upregulation of Prolactin receptor as cancer cells that have disseminated to the lung expand into micrometastases. Secretion of the ligand Prolactin by adjacent lung stromal cells is induced by tumor cell production of the COX-2 synthetic product prostaglandin E-2 (PGE-2). PGE-2 treatment of fibroblasts activates the nuclear orphan receptor NR4A (Nur77), with Prolactin as a major transcriptional target for the NR4A-Retinoid X receptor (RXR) heterodimer. Ectopic expression of Prolactin receptor in mouse cancer cells enhances micrometastasis, while treatment with the COX-2 inhibitor Celecoxib abrogates Prolactin secretion by fibroblasts and reduces tumor initiation. Across multiple human cancers, COX-2, Prolactin, and Prolactin receptor show consistent differential expression in tumor and stromal compartments. Such paracrine crosstalk may thus contribute to the documented efficacy of COX-2 inhibitors in cancer suppression.
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