Prolactin receptor-integrin cross-talk mediated by SIRPα in breast cancer cells

Abstract

The hormone prolactin (PRL) contributes to the pathogenesis of breast cancer in part through its activation of Janus-activated kinase 2 (Jak2)/signal transducer and activator of transcription 5 (Stat5), a PRL receptor (PRLr)-associated pathway dependent on cross-talk signaling from integrins. It remains unclear, however, how this cross-talk is mediated.

Following PRL stimulation, we show that a complex between the transmembrane glycoprotein signal regulatory protein-α (SIRPα) and the PRLr, β(1) integrin, and Jak2 in estrogen receptor-positive (ER(+)) and ER(-) breast cancer cells is formed.

Overexpression of SIRPα in the absence of collagen 1 significantly decreased PRL-induced gene expression, phosphorylation of PRLr-associated signaling proteins, and PRL-stimulated proliferation and soft agar colony formation. In contrast, overexpression of SIRPα in the presence of collagen 1 increased PRL-induced gene expression; phosphorylation of Jak2, Stat5, and Erk; and PRL-stimulated cell growth. Interestingly, overexpression of a tyrosine-deficient SIRPα (SIRPα-4YF) prevented the signaling and phenotypic effects mediated by wild-type SIRPα.

Furthermore, overexpression of a phosphatase-defective mutant of Shp-2 or pharmacologic inhibition of Shp-2 produced effects comparable with that of SIRPα-4YF. However, the tyrosine phosphorylation of SIRPα was unaffected in the presence or absence of collagen 1.

These data suggest that SIRPα modulates PRLr-associated signaling as a function of integrin occupancy predominantly through the alteration of Shp-2 activity.

This PRLr-SIRPα-integrin complex may therefore provide a basis for integrin-PRLr cross-talk and contribute to the biology of breast cancer.

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See also:

- Official Web Site: The Di Bella Method;

- 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);

- 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;

- Recurrent Glioblastoma Multiforme (grade IV – WHO 2007): a case of complete objective response achieved by means of the concomitant administration of Somatostatin and Octreotide – Retinoids – Vitamin E – Vitamin D3 – Vitamin C – Melatonin – D2 R agonists (Di Bella Method – DBM) associated with Temozolomide;

- The Di Bella Method DBM improved survival objective response and performance status in a retrospective observational clinical study on 23 tumours of the head and neck;

- Chronic Lymphocytic Leukemia: Long-Lasting Remission with Combination of Cyclophosphamide, Somatostatin, Bromocriptine, Retinoids, Melatonin, and ACTH;

- Neuroblastoma: Complete objective response to biological treatment;

- Oesophageal squamocellular carcinoma: a complete and objective response;

- The Di Bella Method (DBM) in the treatment of prostate cancer: a preliminary retrospective study of 16 patients and a review of the literature.