Abstract 1621: Contactin 1 (CNTN1) promotes prostate cancer tumorigenesis in transgenic models Conference Paper uri icon

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abstract

  • Abstract Background: Prostate cancer (PCa) is one of the most common male-specific malignancies in developed country. The progression of PCa involves complex mechanisms. Contactin 1 (CNTN1) is a neural cell adhesion protein reported to promote lung cancer metastasis and associate with poor prognosis in several cancers. In view of our recent publication reporting CNTN1 as a novel factor promoting PCa metastasis, we have constructed prostate-specific CNTN1 overexpression (CNTN1TG/TG) and PTEN−/− mice to explore CNTN1's role in PC tumorigenesis and progression. Materials and Methods: CNTN1 transgenic C57BL/6 mice was constructed by insertion of a transgene unit into the intron of Rosa26 locus. The CNTN1 transgene (TG) cassette consists of a CAG promoter, a STOP unit flanked by two LoxP sites, followed by CNTN1, which will only be expressed upon removal of the STOP unit by Cre recombinase. The homozygous CNTN1STOP-TG/STOP-TG [without transgene (TG) expression] mice were crossed with prostate-specific Cre mice (PB-Cre4). Prostate expression of CNTN1 was clearly demonstrated only in CNTN1TG/− and CNTN1TG/TG mice but not in CNTN1STOP-TG/STOP-TG animals. In a similar system, PTENflox/flox were crossed with PB-Cre4 to generate prostate-specific PTEN−/- mice. At 21-weeks old when invasive tumors were formed, PTEN−/− mice were surgically castrated and maintained for another 12 weeks to construct the castration-resistant prostate cancer (CRPC) model. Results: At 12-weeks old both CNTN1TG/- and CNTN1TG/TG mice developed hyperplasia in the prostate, evident by an increase in cellularity, nuclear crowding, and mild dysplasia. This supports CNTN1's role in PCa tumorigenesis as prostate epithelial hyperplasia in transgenic mice is a well-regarded precursor of PCa. In line of this observation, immunohistochemistry showed upregulation of proliferation marker Ki67 and AKT phosphorylation at serine 473 (indicative of AKT activation) in the prostate of CNTN1TG/TG compared to control CNTN1STOP-TG/STOP-TG (without Cre) mice. In androgen-sensitive LNCaP cells stably expressing CNTN1, an upregulation of prostate-specific antigen (PSA), a well-regarded AR target, was observed both with and without androgen deprivation. This suggest that CNTN1 likely initiates PCa and contributes to its progression through networks involving AR signaling. The oncogenic role of CNTN1 in association with PTEN deficiency was explored using prostate-specific PTEN−/− mice which recapitulate most clinical features of PCa, including the development of castration-resistant PCa (CRPC). The expression of CNTN1 was undetectable in age-matched C57BL/6 mice but was evident in tumors produced in intact PTEN−/− mice and was further upregulated in CRPC tumors generated in castrated PTEN−/- mice. These observations are consistent with CNTN1-induced AKT activation observed in PCa cells and in CNTN1TG/TG animals. Conclusions: Collectively, these results suggest a role of CNTN1 in promoting PCa tumorigenesis and progression. Evidently, our CNTN1 transgenic mice developed a precancerous lesion of PCa. The oncogenic potential of CNTN1 is further supported by its stimulation of LNCaP cell proliferation. This research provides functional evidence for CNTN1 as an important PCa promoting factor and established a novel transgenic mouse model for PCa; this model may greatly facilitate future PCa research and drug development. Citation Format: Yan Jennifer Gu, Wenjuan Mei, Geoffrey A. Wood, Damu Tang. Contactin 1 (CNTN1) promotes prostate cancer tumorigenesis in transgenic models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1621.

authors

  • Gu, Yan Jennifer
  • Mei, Wenjuan
  • Wood, Geoffrey A
  • Tang, Damu

publication date

  • August 15, 2020