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Inflammation and stem markers association to PIM1/PIM2 kinase-induced tumors in breast and uterus

2017; Impact Journals LLC; Volume: 8; Issue: 35 Linguagem: Inglês

10.18632/oncotarget.19438

1949-2553

Manuel P. Jiménez-García, Antonio Lucena-Cacace, María-José Robles-Frías, Irene Ferrer, Maja Narlik‐Grassow, Carmen Blanco‐Aparicio, Amancio Carnero,

Phytochemical compounds biological activities

// Manuel-Pedro Jiménez-García 1 , Antonio Lucena-Cacace 1 , María-José Robles-Frías 1 , Irene Ferrer 1 , Maja Narlik-Grassow 2 , Carmen Blanco-Aparicio 2 and Amancio Carnero 1, 3 1 Instituto de Biomedicina de Sevilla, IBIS, Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Consejo Superior de Investigaciones Científicas, Seville, Spain 2 Experimental Therapeutics Programme, Spanish National Cancer Centre (CNIO), Madrid, Spain 3 CIBER de Cáncer, Instituto de Salud Carlos III, Pabellón 11, Planta 0, Madrid, Spain Correspondence to: Amancio Carnero, email: acarnero-ibis@us.es Keywords: PIM kinases, conditional transgenic mice, oncogenesis, reproductive system tumors, mammary tumors Received: May 26, 2017 Accepted: July 11, 2017 Published: July 22, 2017 ABSTRACT The PIM family of Ser/Thr kinase proteins has been implicated in tumorigenesis at different levels. PIM proteins are overexpressed in several tumor types and have been associated with chemoresistance. However, their role in hormone-dependent female tissues has not been explored, especially in the uterus, breast and ovary. We generated conditional transgenic mice with confined expression of human PIM1 or PIM2 genes in these tissues. We characterized the tumoral response to these genetic alterations corroborating their role as oncogenes since they induce hyperproliferation in all tissues and tumors in mammary gland and uterus. Furthermore, we observed a high degree of inflammatory infiltration in these tissues of transgenic mice accompanied by NFAT and mTOR activation and IL6 expression. Moreover, PIM1/2 were overexpressed in human breast, uterine and ovarian tumors, correlating with inflammatory features and stem cell markers. Our data suggest that PIM1/2 kinase overexpression provoke tissue alterations and a large IL6-dependent inflammatory response that may act synergistically during the process of tumorigenesis. The possible end-point is an increased percentage of cancer stem cells, which may be partly responsible for the therapy resistance found in tumors overexpressing PIM kinases.