Prolactin Induces Up-regulation of Its Cognate Receptor in Breast Cancer Cells Via Transcriptional Activation of Its Generic Promoter by Cross-talk Between ERα and STAT5

Overview

Journal Oncotarget

Specialty Oncology

Date 2014 Sep 7

PMID 25193864

Citations 14

Authors

Raghuveer Kavarthapu

Chon-Hwa Tsai Morris

Maria L Dufau

Affiliations

Soon will be listed here.

Abstract

Prolactin (PRL) serves a critical role in breast cancer progression via activation of its cognate receptor. These studies reveal up-regulation of PRLR gene expression by PRL in absence of estradiol in MCF-7 and T47D breast cancer cells. PRL/PRLR via activation of STAT5 that binds a GAS-element in the PRLR gene and the participation of ERα stimulates PRLR transcription/expression. PRL/PRLR induces phosphorylation of ERα through the JAK2/PI3K/MAPK/ERK and JAK2/HER2 activated pathways. The increased recruitment of phospho-ERα, induced by PRL to Sp1 and C/EBPβ at PRLR promoter sites is essential for PRL-induced PRLR transcription. This recruitment is prevented by blockade of PRL expression using RNA interference or ERα phosphorylation using specific inhibitors of PI3K and ERK. Direct evidence is provided for local actions of PRL, independent of estradiol, in the up-regulation of PRLR transcription/expression by an activation-loop between STAT5 and the phospho-ERα/Sp1/C/EBPβ complex with requisite participation of signaling mechanisms. PRL's central role in the up-regulation of PRLR maximizes the action of the endogenous hormone. This study offers mechanistically rational basis for invasiveness fueled by prolactin in refractory states to adjuvant therapies in breast cancer.

Citing Articles

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Stem Cell-Associated Signatures Help to Predict Diagnosis and Prognosis in Ovarian Serous Cystadenocarcinoma.

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

Kavarthapu R, Dufau M Front Endocrinol (Lausanne). 2022; 13:949396.

PMID: 36187116 PMC: 9520000. DOI: 10.3389/fendo.2022.949396.

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References

Wang Y, Cheng C . ERalpha and STAT5a cross-talk: interaction through C-terminal portions of the proteins decreases STAT5a phosphorylation, nuclear translocation and DNA-binding. FEBS Lett. 2004; 572(1-3):238-44. DOI: 10.1016/j.febslet.2004.06.098. View

Riggins R, Thomas K, Ta H, Wen J, Davis R, Schuh N . Physical and functional interactions between Cas and c-Src induce tamoxifen resistance of breast cancer cells through pathways involving epidermal growth factor receptor and signal transducer and activator of transcription 5b. Cancer Res. 2006; 66(14):7007-15. DOI: 10.1158/0008-5472.CAN-05-3952. View

Wennbo H, Tornell J . The role of prolactin and growth hormone in breast cancer. Oncogene. 2000; 19(8):1072-6. DOI: 10.1038/sj.onc.1203349. View

Dong J, Tsai-Morris C, Dufau M . A novel estradiol/estrogen receptor alpha-dependent transcriptional mechanism controls expression of the human prolactin receptor. J Biol Chem. 2006; 281(27):18825-36. DOI: 10.1074/jbc.M512826200. View

Bonneterre J, Peyrat J, Beuscart R, Demaille A . Biological and clinical aspects of prolactin receptors (PRL-R) in human breast cancer. J Steroid Biochem Mol Biol. 1990; 37(6):977-81. DOI: 10.1016/0960-0760(90)90453-r. View

Junttila T, Akita R, Parsons K, Fields C, Lewis Phillips G, Friedman L . Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941. Cancer Cell. 2009; 15(5):429-40. DOI: 10.1016/j.ccr.2009.03.020. View

Sarwar N, Kim J, Jiang J, Peston D, Sinnett H, Madden P . Phosphorylation of ERalpha at serine 118 in primary breast cancer and in tamoxifen-resistant tumours is indicative of a complex role for ERalpha phosphorylation in breast cancer progression. Endocr Relat Cancer. 2006; 13(3):851-61. DOI: 10.1677/erc.1.01123. View

Touraine P, Martini J, Zafrani B, Durand J, Labaille F, Malet C . Increased expression of prolactin receptor gene assessed by quantitative polymerase chain reaction in human breast tumors versus normal breast tissues. J Clin Endocrinol Metab. 1998; 83(2):667-74. DOI: 10.1210/jcem.83.2.4564. View

de Leeuw R, Neefjes J, Michalides R . A role for estrogen receptor phosphorylation in the resistance to tamoxifen. Int J Breast Cancer. 2012; 2011:232435. PMC: 3262574. DOI: 10.4061/2011/232435. View

10.

OLeary K, Jallow F, Rugowski D, Sullivan R, Sinkevicius K, Greene G . Prolactin activates ERα in the absence of ligand in female mammary development and carcinogenesis in vivo. Endocrinology. 2013; 154(12):4483-92. PMC: 3836081. DOI: 10.1210/en.2013-1533. View

11.

Yamauchi T, Yamauchi N, Ueki K, Sugiyama T, Waki H, Miki H . Constitutive tyrosine phosphorylation of ErbB-2 via Jak2 by autocrine secretion of prolactin in human breast cancer. J Biol Chem. 2000; 275(43):33937-44. DOI: 10.1074/jbc.M000743200. View

12.

Dawood S, Cristofanilli M . Endocrine resistance in breast cancer: what really matters?. Ann Oncol. 2007; 18(8):1289-91. DOI: 10.1093/annonc/mdm359. View

13.

Hu Z, Zhuang L, Meng J, Tsai-Morris C, Dufau M . Complex 5' genomic structure of the human prolactin receptor: multiple alternative exons 1 and promoter utilization. Endocrinology. 2002; 143(6):2139-42. DOI: 10.1210/endo.143.6.8949. View

14.

Arteaga C, Sliwkowski M, Osborne C, Perez E, Puglisi F, Gianni L . Treatment of HER2-positive breast cancer: current status and future perspectives. Nat Rev Clin Oncol. 2011; 9(1):16-32. DOI: 10.1038/nrclinonc.2011.177. View

15.

Meng J, Tsai-Morris C, Dufau M . Human prolactin receptor variants in breast cancer: low ratio of short forms to the long-form human prolactin receptor associated with mammary carcinoma. Cancer Res. 2004; 64(16):5677-82. DOI: 10.1158/0008-5472.CAN-04-1019. View

16.

Hu Z, Meng J, Dufau M . Isolation and characterization of two novel forms of the human prolactin receptor generated by alternative splicing of a newly identified exon 11. J Biol Chem. 2001; 276(44):41086-94. DOI: 10.1074/jbc.M102109200. View

17.

John S, Vinkemeier U, Soldaini E, Darnell Jr J, Leonard W . The significance of tetramerization in promoter recruitment by Stat5. Mol Cell Biol. 1999; 19(3):1910-8. PMC: 83984. DOI: 10.1128/MCB.19.3.1910. View

18.

Finidori J, Kelly P . Cytokine receptor signalling through two novel families of transducer molecules: Janus kinases, and signal transducers and activators of transcription. J Endocrinol. 1995; 147(1):11-23. DOI: 10.1677/joe.0.1470011. View

19.

Bjornstrom L, Kilic E, Norman M, Parker M, Sjoberg M . Cross-talk between Stat5b and estrogen receptor-alpha and -beta in mammary epithelial cells. J Mol Endocrinol. 2001; 27(1):93-106. DOI: 10.1677/jme.0.0270093. View

20.

WELSCH C, Nagasawa H . Prolactin and murine mammary tumorigenesis: a review. Cancer Res. 1977; 37(4):951-63. View