*4.4. Endocrine Modulation*

Considerable epidemiological evidence has shown that fat-containing diets may increase the risk of certain hormone-dependent conditions in men via its e ffects on hormone metabolism [90]. Hormonal modulation has been one of the proposed mechanisms associated with diet- and/or obesity-induced prostate cancer carcinogenesis [8,9] given that sex hormones play a key role during normal and

cancerous prostate growth and development. Two transgenic mouse studies showed that omega-3 fatty acids slowed prostate tumor growth through the modulation of sex steroid pathways. In the C3 (1) Tag transgenic mice study, the lowering testosterone, estradiol, and androgen receptor levels by the action of omega-3 fatty acids promoted apoptosis and suppressed prostate epithelial cell proliferation [29]. Another study demonstrated that omega-3 PUFA treatment slowed castration-resistant tumor growth and accelerated androgen receptor protein degradation [34]. A recent study showed that although serum cholesterol reduction did not significantly a ffect the rate of adenocarcinoma development in the PTEN-null transgenic mouse model of prostate cancer [78], it lowered intraprostatic androgens and slowed tumor growth. These results sugges<sup>t</sup> that fat-containing diets, especially those that modulate of omega-3 fatty acid content, may potentially modulate intraprostatic hormonal status associated with cancerous tumor growth and progression. In the TRAMP-C1 allograft study, HFD increased tumor growth and serum estradiol levels [55]. The study also showed that intratumoral C-terminal-binding protein 1 (CtBP1) controls the transcription of aromatase (CYP19A), a key enzyme that converts androgens to estrogens, and was overexpressed with increased TRAMP-C1 allograft tumor growth in mice receiving a HFD. In another study, Moiola et al. found that mice with CtBP1-depleted PC-3 xenografts developed significantly smaller tumors than those inoculated with PC-3 control cells [38]. These results sugges<sup>t</sup> that CtBP1 have the potential to be a key transcriptional factor associated with intratumoral hormonal modulation and HFD-induced prostate cancer growth.
