Abstract A20: Pin1 as a regulator of multiple targets of cell growth in lung cancer
Authors: Boffo Silvia , D'Angelo Barbara , Klein-Szanto Andres J. , Macaluso Marcella , Giordano Antonio 
Published: May 2018

Abstract
Peptidylprolyl isomerase 1 (Pin1), a peptidyl-prolyl cis/trans isomerase, is overexpressed in many different cancer types and has been shown to serve as a poor prognostic factor in the lung. Furthermore, it has been indicated that overexpression of Pin1 correlates with increased expression of both p53 and MDM2 in human adenocarcinoma. However, the exact molecular mechanism by which Pin1 increases tumor cell proliferation is still unknown. Here, we show that Pin1 increases the occurrence of adenocarcinoma in a mouse model. Moreover, we assessed the hypothesis that Pin1 increases lung tumorigenesis by altering the function of alternative cell cycle regulators, perhaps affecting their phosphorylation status.
Recently, several genetically engineered mouse models of lung adenocarcinoma have been developed to mimic the genetic and phenotypic features of the human disease, including activating mutations in K-RAS and loss-of-function mutations in p53. To fully understand the role of Pin1 in lung cancer, we developed a mouse model of Pin1 overexpression in the context of mutant K-RAS and p53 loss of function in immunocompetent mice. This model was obtained by an intratracheal delivery of lentiviral Cre-recombinase, which activates the expression of a mutant oncogene K-RAS (G12D) and a truncated p53, combined with ectopic overexpression of Pin1.
Changes in protein expression and cellular localization of the proliferative index Ki67, RB1, RB2, and cdk2, upon Pin1 ectopic overexpression, were evaluated in sections of paraffin-embedded lung tumor tissue from our conditional mouse model at different time points, and using an immunohistochemical (IHC) approach. To evaluate the effects of Pin1 on lung tumor cell proliferation specific for cell cycle regulatory pathways, we also performed Western blot (WB) analysis using frozen tissue collected from the same conditional mouse model.
The histologic classification of each samples was made on H&E-stained sections by A.K.S., a veterinary pathologist with extensive experience in murine lung pathology.
Our results confirmed that overexpression of Pin1 correlates with increased expression of both p53 and MDM2, and more importantly indicated that Pin1 raises the occurrence of adenocarcinoma in vivo. Specifically, we found that Pin1 increases lung tumorigenesis by altering the phosphorylation status of alternative cell cycle regulatory pathways irrespective of the p53-cell cycle regulatory system.
In conclusion, in our model the overexpression of Pin1 contributed to a higher incidence of lung adenocarcinoma, suggesting Pin1 as having a promoting effect toward carcinogenesis.
Lung cancer continues to be one of the leading causes of cancer deaths in the US and, while surgical resection offers the best treatment option, oftentimes the cancer is not detected early enough for surgery to be effective. For this reason, identifying molecular targets centered on the early stages of lung cancer development that will aid in the advancement of treatments is of the utmost importance. We believe that Pin1, and its related targets, offer a unique therapeutic option to alter the cancer cell cycle machinery.
Citation Format: Silvia Boffo, Barbara D'Angelo, Andres J. Klein-Szanto, Marcella Macaluso, Antonio Giordano. Pin1 as a regulator of multiple targets of cell growth in lung cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr A20.