Role of EGF/ERBB1 in the transcriptional regulation of the prolactin receptor independent of estrogen and prolactin in breast cancer cells

Abstract

Prolactin receptor (PRLR) and epidermal growth factor receptor (EGFR/ERBB1) have important roles in the physiology of the human breast and in the etiology and progression of breast cancer.

Our present studies in MCF-7 cells revealed that EGF induces up-regulation of PRLR via activation of EGFR signalling pathways leading to activation of estrogen receptor α (ERα). EGF treatment of MCF-7 cells cultured in absence of estradiol induced expression of PRLR that was consistent with the activation of PRLR generic promoter (hPIII). These were abolished by ERα antagonist and siRNA, indicating involvement of ERα in EGF-induced hPIII promoter activity. MEK/MAPK and PI3K/AKT pathways participate in the phosphorylation of ERα induced by EGF/EGFR. PI3K and MEK inhibitors abolished EGF-induced PRLR promoter activity. Increased recruitment of non-DNA bound unliganded ERα to Sp1 and C/EBPβ bound to their sites at hPIII induced by EGF was abrogated by ERα siRNA demonstrating the requisite role of phospho-ERα in PRLR upregulation. EGF/EGFR, independent of endogenous prolactin induced phosphorylation of STAT5b with participation of c-SRC and recruitment of STAT5b:STAT5b to a GAS site at hPIII. STAT5b interaction with ERα was essential for stable phospho-ERα recruitment to the SP1/CEBPβ complex.

These studies indicate a role for paracrine EGF via EGFR independent of estrogen and prolactin in the transcriptional activation of PRLR gene expression and its contribution to high levels of PRLRs in breast cancer.

These by maximizing the actions of endogenous prolactin could have a role in cancer progression and resistance to endocrine therapy.

 

About this publication.

See also:

- Official Web Site: The Di Bella Method;

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- The Di Bella Method (A Fixed Part - Bromocriptine and/or Cabergoline);

- The Di Bella Method (A Fixed Part - Cyclophosphamide 50mg tablets and/or Hydroxyurea 500mg tablets, one or two per day);

- The Di Bella Method (A Fixed Part - Somatostatin, Octreotide, Sandostatin LAR, analogues and/or derivatives);

- Somatostatin in oncology, the overlooked evidences - In vitro, review and in vivo publications;

- Publication, 2018 Jul: Over-Expression of GH/GHR in Breast Cancer and Oncosuppressor Role of Somatostatin as a Physiological Inhibitor (from Di Bella's Foundation);

- Publication, 2018 Sep: The over-expression of GH/GHR in tumour tissues with respect to healthy ones confirms its oncogenic role and the consequent oncosuppressor role of its physiological inhibitor, somatostatin: a review of the literature (from Di Bella's Foundation);

- Publication, 2019 Aug: The Entrapment of Somatostatin in a Lipid Formulation: Retarded Release and Free Radical Reactivity (from Di Bella's Foundation);

- Publication, 2019 Sep: Effects of Somatostatin and Vitamin C on the Fatty Acid Profile of Breast Cancer Cell Membranes (from Di Bella's Foundation);

- Publication, 2019 Sep: Effects of somatostatin, curcumin, and quercetin on the fatty acid profile of breast cancer cell membranes (from Di Bella's Foundation);

- Publication, 2020 Sep: Two neuroendocrine G protein-coupled receptor molecules, somatostatin and melatonin: Physiology of signal transduction and therapeutic perspectives (from Di Bella's Foundation);

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- The Synergism of Somatostatin, Melatonin, Vitamins Prolactin and Estrogen Inhibitors Increased Survival, Objective Response and Performance Status In 297 Cases of Breast Cancer;

- Complete objective response, stable for 5 years, with the Di Bella Method, of multiple-metastatic carcinoma of the breast;

- Evaluation of the safety and efficacy of the first-line treatment with somatostatin combined with melatonin, retinoids, vitamin D3, and low doses of cyclophosphamide in 20 cases of breast cancer: a preliminary report;

- The Di Bella Method (DBM) improved survival, objective response and performance status in a retrospective observational clinical study on 122 cases of breast cancer;

- Complete objective response to biological therapy of plurifocal breast carcinoma.