Gain-of-function Prolactin Receptor Variants Are Not Associated With Breast Cancer and Multiple Fibroadenoma Risk

Chakhtoura, Zeina; Laki, Fatima; Bernadet, Marie; Cherifi, Ibtissem; Chiche, Aurélie; Pigat, Natascha; Bernichtein, Sophie; Courtillot, Carine; Boutillon, Florence; Bièche, Ivan; Vacher, Sophie; Tanguy, Marie‐Laure; Bissery, Anne; Grouthier, Virginie; Camparo, Philippe; Foretz, Marc; Cruzeiro, Marcio Do; Pierre, Rémi; Rakotozafy, F; Tichet, Jean; Tejedor, Isabelle; Guidotti, Jacques-Emmanuel; Sigal‐Zafrani, Brigitte; Goffin, Vincent; Touraine, Philippe

doi:10.1210/jc.2016-2372

Cited by 11 publications

(8 citation statements)

References 35 publications

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“…The low-frequency PRLR variants Ile76Val and Ile146Leu, which did not alter PRLR function or only altered PRLR function at supraphysiological prolactin concentrations (Fig. 4), respectively, likely represent PRLR benign polymorphisms, without clinical significance, and this is in agreement with recent reports from studies of women with breast cancer and fibroadenomas (43). The rare Glu376Gln PRLR variant, which did not alter PRLR function (Fig.…”

Section: Discussionsupporting

confidence: 91%

Association of prolactin receptor (PRLR) variants with prolactinomas

Gorvin

Newey

Rogers

et al. 2018

Human Molecular Genetics

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Prolactinomas are the most frequent type of pituitary tumors, which represent 10–20% of all intracranial neoplasms in humans. Prolactinomas develop in mice lacking the prolactin receptor (PRLR), which is a member of the cytokine receptor superfamily that signals via Janus kinase-2-signal transducer and activator of transcription-5 (JAK2-STAT5) or phosphoinositide 3-kinase-Akt (PI3K-Akt) pathways to mediate changes in transcription, differentiation and proliferation. To elucidate the role of the PRLR gene in human prolactinomas, we determined the PRLR sequence in 50 DNA samples (35 leucocytes, 15 tumors) from 46 prolactinoma patients (59% males, 41% females). This identified six germline PRLR variants, which comprised four rare variants (Gly57Ser, Glu376Gln, Arg453Trp and Asn492Ile) and two low-frequency variants (Ile76Val, Ile146Leu), but no somatic variants. The rare variants, Glu376Gln and Asn492Ile, which were in complete linkage disequilibrium, and are located in the PRLR intracellular domain, occurred with significantly higher frequencies ( P < 0.0001) in prolactinoma patients than in 60 706 individuals of the Exome Aggregation Consortium cohort and 7045 individuals of the Oxford Biobank. In vitro analysis of the PRLR variants demonstrated that the Asn492Ile variant, but not Glu376Gln, when compared to wild-type (WT) PRLR, increased prolactin-induced pAkt signaling (>1.3-fold, P < 0.02) and proliferation (1.4-fold, P < 0.02), but did not affect pSTAT5 signaling. Treatment of cells with an Akt1/2 inhibitor or everolimus, which acts on the Akt pathway, reduced Asn492Ile signaling and proliferation to WT levels. Thus, our results identify an association between a gain-of-function PRLR variant and prolactinomas and reveal a new etiology and potential therapeutic approach for these neoplasms.

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Section: Discussionsupporting

confidence: 91%

Association of prolactin receptor (PRLR) variants with prolactinomas

Gorvin

Newey

Rogers

et al. 2018

Human Molecular Genetics

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“…On the other hand, I. Hachim et al found that the expression of PRL-R is reduced in invasive BC (21.4%), compared with BBT (80%) and carcinoma in situ (60%) (p = 0.003498) [21]. There was also no association between the gene polymorphism of PRL-R (PRLRI146L and PRLRI176V variants) with breast tumor growth and proliferation [22].…”

Section: Discussionmentioning

confidence: 97%

The Expression of Prolactin Receptors in Benign Breast Tumors Is Not Associated with Serum Prolactin Level

Kolomiiets

Yazykov

Piddubnyi

et al. 2021

JCM

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The role of prolactin (PRL) and its receptors in the initiation and development of benign breast tumors (BBT) has not been sufficiently studied. An imbalance in the system of hormone homeostasis is crucial in the development of BBT. In particular, an association between elevated prolactin levels and the development of BBT has been reported. Our study showed no significant differences between PRL receptor (PRL-R) expression in BBT tissue under normal and elevated serum PRL levels. There was also no significant correlation between age, PRL-R expression in BBT tissue, intact tissue, and PRL level in the serum. There was a strong significant correlation (p < 0.01; r = 0.92) between PRL-R expression in BBT samples and intact breast tissue, which did not depend on the serum PRL level. There was also no significant difference in the expression of the proliferative marker Ki-67 in BBT tissues from women with normal and elevated levels of serum PRL (p > 0.05). No signs of PRL and its receptors were detected in the BBT cystic fluid women with elevated serum PRL levels. In summary, our prospective study showed that the expression of PRL-R in the tissue of BBT and physiological breast tissue does not depend on the level of serum PRL.

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“…The two SNPs PRLR-I76V and I146L demonstrate constitutive receptor activity, and one of the SNPs (PRLRI146L) correlates with benign breast disease in a patient cohort, but these patients did not have high levels of serum PRL ( 22 , 66 ). However, in subsequent study these SNPs in the PRLR gene were found not to be associated with breast cancer and multiple fibroadenoma ( 67 ). In another study, SNPs were found in PRL , and PRLR genes were associated with breast cancer metastasis in Taiwanese women ( 68 ).…”

Section: Role Of Prl/prlr Signaling In Breast Cancermentioning

confidence: 96%

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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Gain-of-function Prolactin Receptor Variants Are Not Associated With Breast Cancer and Multiple Fibroadenoma Risk

Abstract: PRLR and PRLR variants are not associated with breast cancer or MFA risk. However, one cannot exclude that low but sustained PRLR signaling may facilitate or contribute to pathological development driven by oncogenic pathways. Long-term patient follow-up should help to address this issue.

Cited by 11 publications

References 35 publications

Association of prolactin receptor (PRLR) variants with prolactinomas

Association of prolactin receptor (PRLR) variants with prolactinomas

The Expression of Prolactin Receptors in Benign Breast Tumors Is Not Associated with Serum Prolactin Level

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

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