Mechanisms underlying the link between obesity and neoplastic progression

The mechanistic link between prostate cancer and obesity is elusive. Pten+/-- mice with monoallelic mutation of Phosphatase and TENsin homolog (Pten), a well-characterized tumor suppressor gene, develop murine prostatic intraepithelial neoplasia (mPIN) lesions with low penetrance. We observed that protein levels of another tumor suppressor gene, the CarcinoEmbryonic Antigen-related Cell Adhesion Molecule 1 (CEACAM1), are elevated in our Pten +/-- mouse prostates. When Pten+/-- mice were fed with high fat diet (HF) beginning at weaning and until sacrifice at ages 4 and 7 months, they exhibited more progressive mouse prostate intraepithelial neoplasia (mPIN) lesions and significantly greater visceral obesity compared to age-matched regular chow-fed controls. With CEACAM1 being significantly reduced in metastatic prostate cancer and in obese humans, we hypothesized that global deletion of Ceacam1 would remove the protection against further progression to advanced mPIN lesions in Pten+/-- mice. High-fat intake for 6 months induced severe mPIN and invasive prostate adenocarcinoma in 21% of Pten +/-- mice whereas the penetrance was 46% for the mice with biallelic deletion of Ceacam1. At the same time, we observed a marked increase in CEACAM1 in prostate in high fat fed Pten+/-- mice compared to regular diet controls. Quantitative RT-PCR analysis showed that HF diet increases both CEACAM1 short (S) and long (L) isoforms in Pten mice leading to an S:L of 3.4 to 1. Because the tumor suppression activity of CEACAM1-L is regulated by a balanced S:L ratio, it is possible that this shift in S:L ratio by HF synergizes with Pten loss to cause a more progressive neoplastic form as compared to Pten mice on regular diet. The mechanism of this synergy between S:L imbalances and Pten loss is unclear. It could be related to (A) increased angiogenesis from endothelial CEACAM1, or (B) a dominant-negative effect on tumor suppression by the higher relative content of the short isoform in epithelial cells. Both possibilities warrant further studies. Taken together, this study suggests that lack of CEACAM1 activity potentiates neoplastic progression caused by Pten haploinsufficiency.