Serine residues 726 and 780 have nonredundant roles regulating STAT5a activity in luminal breast cancer

Woock, Alicia E.; Grible, Jacqueline M; Olex, Amy L.; Harrell, J. Chuck; Zot, Patricija; Idowu, Michael O.; Clevenger, Charles V.

doi:10.1038/s41598-021-92830-8

Cited by 7 publications

(8 citation statements)

References 68 publications

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“…Similar to the results in HeLa cells, distinct single bands were detected in the normal feline mammary gland and feline mammary carcinoma lysates in the blots stained with anti-tSTAT5 antibody. For pSTAT5, although a distinct single band was detected in the normal feline mammary gland lysate, no band was detected in the feline mammary carcinoma lysate [ 20 , 56 ]. β-actin as a loading control was detected as single bands in all lysates from normal feline mammary gland, feline mammary carcinoma, and HeLa cells.…”

Section: Resultsmentioning

confidence: 99%

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Reduction of phosphorylated signal transducer and activator of transcription-5 expression in feline mammary carcinoma

OWAKI,

MURAKAMI,

KATO

et al. 2024

The Journal of Veterinary Medical Science

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Signal transducers and activators of transcription (STAT) is a family of transcription factors involved in various normal physiological cellular processes. Moreover, STATs have been recently identified as novel therapeutic targets for various human tumors. STAT3, STAT5a, and STAT6 have been suggested to be involved in tumorigenesis in human breast cancer. Owing to the similarity between feline mammary carcinomas (FMCs) and human breast cancers, these factors may play an important role in FMCs. However, studies on the expression of STATs in animal tumors are limited.Therefore, in this study, we aimed to characterize the expression of total STAT5 (tSTAT5) and phosphorylated STAT5 (pSTAT5) in FMCs, feline mammary adenomas, non-neoplastic proliferative mammary gland lesions, and normal feline mammary glands using immunohistochemistry. High expression of tSTAT5 was observed in the cytoplasm of all the samples assessed in this study.Moreover, high expression of tSTAT5 was observed in the nucleus; however, its levels varied depending on the lesion. The percentage of pSTAT5-nuclear positive cells varied among normal feline mammary glands (40.1 ± 25.1%), and non-neoplastic lesions, including mammary hyperplasia (43.2 ± 28.6%) and fibroadenomatous changes (18.0 ± 13.6%). Moreover, the percentage of pSTAT5-nuclearpositive cells in feline mammary adenomas was 24.5 ± 19.2%, which was significantly reduced in feline mammary carcinomas (2.4 ± 5.6%), regardless of histopathological subtype. This study suggests that decreased STAT5 activity may be involved in the development and malignant progression of feline mammary carcinomas.

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Section: Resultsmentioning

confidence: 99%

“…Therefore, in this study, we used the anti-STAT5a antibody used in previous studies [16,56]. Furthermore, cross-reactivity of both STAT5a and pSTAT5 antibodies was confirmed by western blotting because cross-reactivity has not yet been reported in feline tissues.…”

Section: Discussionmentioning

confidence: 99%

Reduction of phosphorylated signal transducer and activator of transcription-5 expression in feline mammary carcinoma

OWAKI,

MURAKAMI,

KATO

et al. 2024

The Journal of Veterinary Medical Science

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“…Therefore, future studies should assess the variation in breast cancer risk by pSTAT5a and pSTAT5b, particularly in premenopausal women. Additionally, we evaluated tyrosine phosphorylated STAT5, however unphosphorylated STAT5 as well as serine-phosphorylated STAT5 may have varying associations with breast cancer risk and should be considered in future studies [ 38 , 39 ]. Similarly, our assessment of PRLR did not distinguish between different isoforms of this receptor, which have been shown to have differential effects on downstream STAT5 signaling [ 40 ], suggesting that future studies should separately evaluate the most oncogenic isoforms.…”

Section: Discussionmentioning

confidence: 99%

Prolactin levels and breast cancer risk by tumor expression of prolactin-related markers

et al. 2023

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Background Higher circulating prolactin has been associated with increased breast cancer risk. Prolactin binding to the prolactin receptor (PRLR) can activate the transcription factor STAT5, thus, we examined the association between plasma prolactin and breast cancer risk by tumor expression of PRLR, STAT5, and the upstream kinase JAK2. Methods Using data from 745 cases and 2454 matched controls in the Nurses’ Health Study, we conducted polytomous logistic regression to examine the association between prolactin (> 11 ng/mL vs. ≤ 11 ng/mL) measured within 10 years of diagnosis and breast cancer risk by PRLR (nuclear [N], cytoplasmic [C]), phosphorylated STAT5 (pSTAT5; N, C), and phosphorylated JAK2 (pJAK2; C) tumor expression. Analyses were conducted separately in premenopausal (n = 168 cases, 765 controls) and postmenopausal women (n = 577 cases, 1689 controls). Results In premenopausal women, prolactin levels > 11 ng/mL were positively associated with risk of tumors positive for pSTAT5-N (OR 2.30, 95% CI 1.02–5.22) and pSTAT5-C (OR 1.64, 95% CI 1.01–2.65), but not tumors that were negative for these markers (OR 0.98, 95% CI 0.65–1.46 and OR 0.73, 95% CI 0.43–1.25; p-heterogeneity = 0.06 and 0.02, respectively). This was stronger when tumors were positive for both pSTAT5-N and pSTAT5-C (OR 2.88, 95% CI 1.14–7.25). No association was observed for PRLR or pJAK2 (positive or negative) and breast cancer risk among premenopausal women. Among postmenopausal women, plasma prolactin levels were positively associated with breast cancer risk irrespective of PRLR, pSTAT5, or pJAK2 expression (all p-heterogeneity ≥ 0.21). Conclusion We did not observe clear differences in the association between plasma prolactin and breast cancer risk by tumor expression of PRLR or pJAK2, although associations for premenopausal women were observed for pSTAT5 positive tumors only. While additional studies are needed, this suggests that prolactin may act on human breast tumor development through alternative pathways.

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“…In ER-positive breast cancer, STAT5 expression enhanced the response to hormone therapy and increased the overall survival of patients [reviewed in ( 81 )]. Recent studies have shown that phosphorylation of STAT5a serine residues (S726 and S780) may regulate its activity to promote cell proliferation in MCF-7 cells ( 82 ). Reports have indicated that STAT5 acts as a suppressor of breast cancer invasion and metastatic progression and can be used as a tumor marker of favorable prognosis [reviewed in ( 79 )].…”

Section: Role Of Prl/prlr Signaling In Breast Cancermentioning

confidence: 99%

Prolactin receptor gene transcriptional control, regulatory modalities relevant to breast cancer resistance and invasiveness

Kavarthapu

Dufau

2022

Front. Endocrinol.

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The prolactin receptor (PRLR) is a member of the lactogen/cytokine receptor family, which mediates multiple actions of prolactin (PRL). PRL is a major hormone in the proliferation/differentiation of breast epithelium that is essential for lactation. It is also involved in breast cancer development, tumor growth and chemoresistance. Human PRLR expression is controlled at the transcriptional level by multiple promoters. Each promoter directs transcription/expression of a specific non-coding exon 1, a common noncoding exon 2 and coding exons E3-11. The identification of exon 11 of PRLR led to finding of alternative spliced products and two novel short forms (SF) that can inhibit the long form (LF) of PRLR activity with relevance in physiological regulation and breast cancer. Homo and heterodimers of LF and SF are formed in the absence of PRL that acts as a conformational modifier. Heterodimerization of SF with LF is a major mechanism through which SF inhibits some signaling pathways originating at the LF. Biochemical/molecular modeling approaches demonstrated that the human PRLR conformation stabilized by extracellular intramolecular S−S bonds and several amino acids in the extracellular D1 domain of PRLR SF are required for its inhibitory actions on PRLR LF-mediated functions. Studies in breast cancer cells demonstrated that the transcription of PRLR was directed by the preferentially utilized PIII promoter, which lacks an estrogen responsive element. Complex formation of non-DNA bound ERa dimer with Sp1 and C/EBPb dimers bound to their sites at the PRLR promoter is required for basal activity. Estradiol induces transcriptional activation/expression of the PRLR gene, and subsequent studies revealed the essential role of autocrine PRL released by breast cancer cells and CDK7 in estradiol-induced PRLR promoter activation and upregulation. Other studies revealed stimulation of the PRLR promoter activity and PRLR LF protein by PRL in the absence of estrogen via the STAT5/phospho-ERa activation loop. Additionally, EGF/ERBB1 can induce the transcription of PRLR independent of estrogen and prolactin. The various regulatory modalities contributing to the upregulation of PRLR provide Frontiers in Endocrinology frontiersin.org 01

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Serine residues 726 and 780 have nonredundant roles regulating STAT5a activity in luminal breast cancer

Cited by 7 publications

References 68 publications

Reduction of phosphorylated signal transducer and activator of transcription-5 expression in feline mammary carcinoma

Reduction of phosphorylated signal transducer and activator of transcription-5 expression in feline mammary carcinoma

Prolactin levels and breast cancer risk by tumor expression of prolactin-related markers

Prolactin receptor gene transcriptional control, regulatory modalities relevant to breast cancer resistance and invasiveness

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