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Genetic ablation of FASN attenuates the invasive potential of prostate cancer driven by Pten loss
Author(s) -
Bastos Débora C,
Ribeiro Caroline F,
Ahearn Thomas,
Nascimento Jéssica,
Pakula Hubert,
Clohessy John,
Mucci Lorelei,
Roberts Thomas,
Zanata Silvio M,
Zadra Giorgia,
Loda Massimo
Publication year - 2021
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.5587
Subject(s) - pten , prostate cancer , cancer research , knockout mouse , prostate , carcinogenesis , stromal cell , cancer , gene knockout , tumor suppressor gene , wwox , biology , medicine , apoptosis , pi3k/akt/mtor pathway , suppressor , gene , genetics , receptor
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.