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.
Highlights
The PIM (Provirus integration site for Moloney murine leukemia virus) family of serine/threonine kinases is composed of three different members, PIM1, PIM2 and PIM3, which are highly homologous
PIM1 transgenic mice exhibited a clear percentage of females with macroscopic mammary tumors (Supplementary Figure 1F)
We found an increase in alterations in these organs, hyperplasia, and increased proliferation in the PIM1 and PIM2 transgenic mice
Summary
The PIM (Provirus integration site for Moloney murine leukemia virus) family of serine/threonine kinases is composed of three different members, PIM1, PIM2 and PIM3, which are highly homologous. The expression of PIM genes is induced by a variety of cytokines, growth factors and mitogens [1]. PIM family members are oncogenes that can contribute to tumorigenesis at different levels [1, 3]. These proteins have been labeled as “weak oncogenes” given that their overexpression induces hyperproliferation but no tumors in many cases. These proteins have been shown to greatly enhance the capacity of other genes or chemical carcinogens to induce tumors [1, 3]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
