Genetic ablation of FASN attenuates the invasive potential of prostate cancer driven by Pten loss.

TitleGenetic ablation of FASN attenuates the invasive potential of prostate cancer driven by Pten loss.
Publication TypeJournal Article
Year of Publication2021
AuthorsBastos DC, Ribeiro CF, Ahearn T, Nascimento J, Pakula H, Clohessy J, Mucci L, Roberts T, Zanata SM, Zadra G, Loda M
JournalJ Pathol
Date Published2021 03
KeywordsAdult, Aged, Aged, 80 and over, Animals, Cell Movement, Fatty Acid Synthase, Type I, Humans, Lipogenesis, Male, Mice, Mice, Knockout, Middle Aged, Neoplasm Invasiveness, Prostatic Neoplasms, PTEN Phosphohydrolase

Loss of the tumor suppressor gene Pten in murine prostate recapitulates human carcinogenesis and causes stromal proliferation surrounding murine prostate intraepithelial neoplasia (mPIN), which is reactive to microinvasion. In turn, invasion has been shown to be regulated in part by de novo fatty acid synthesis in prostate cancer. We therefore investigated the effects of genetic ablation of Fasn on invasive potential in prostate-specific Pten knockout mice. Combined genetic ablation of Fasn and Pten reduced the weight and volume of all the prostate lobes when compared to single knockouts. The stromal reaction to microinvasion and the cell proliferation that typically occurs in Pten knockout were largely abolished by Fasn knockout. To verify that Fasn knockout indeed results in decreased invasive potential, we show that genetic ablation and pharmacologic inhibition of FASN in prostate cancer cells significantly inhibit cellular motility and invasion. Finally, combined loss of PTEN with FASN overexpression was associated with lethality as assessed in 660 prostate cancer patients with 14.2 years of median follow-up. Taken together, these findings show that de novo lipogenesis contributes to the aggressive phenotype induced by Pten loss in murine prostate and targeting Fasn may reduce the invasive potential of prostate cancer driven by Pten loss. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Alternate JournalJ Pathol
PubMed ID33166087
PubMed Central IDPMC7898611
Grant ListR01 CA187918 / CA / NCI NIH HHS / United States
U01 CA167552 / CA / NCI NIH HHS / United States
R01 CA131945 / CA / NCI NIH HHS / United States
P50 CA211024 / CA / NCI NIH HHS / United States
Related Faculty: 
Massimo Loda, M.D.

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