Abstract
Data from epidemiological and experimental studies suggest that dietary protein intake may play a role in inhibiting prostate and breast cancer by modulating the IGF/AKT/mTOR pathway. In this study we investigated the effects of diets with different protein content or quality on prostate and breast cancer. To test our hypothesis we assessed the inhibitory effect of protein diet restriction on prostate and breast cancer growth, serum PSA and IGF-1 concentrations, mTOR activity and epigenetic markers, by using human xenograft cancer models. Our results showed a 70% inhibition of tumor growth in the castrate-resistant LuCaP23.1 prostate cancer model and a 56% inhibition in the WHIM16 breast cancer model fed with a 7% protein diet when compared to an isocaloric 21% protein diet. Inhibition of tumor growth correlated, in the LuCaP23.1 model, with decreased serum PSA and IGF-1 levels, down-regulation of mTORC1 activity, decreased cell proliferation as indicated by Ki67 staining, and reduction in epigenetic markers of prostate cancer progression, including the histone methyltransferase EZH2 and the associated histone mark H3K27me3. In addition, we observed that modifications of dietary protein quality, independently of protein quantity, decreased tumor growth. A diet containing 20% plant protein inhibited tumor weight by 37% as compared to a 20% animal dairy protein diet. Our findings suggest that a reduction in dietary protein intake is highly effective in inhibiting tumor growth in human xenograft prostate and breast cancer models, possibly through the inhibition of the IGF/AKT/mTOR pathway and epigenetic modifications.
Highlights
MethodsAndrogen-sensitive and castrate-resistant LuCaP23.1 xenograft models of human prostate cancer
High circulating levels of insulin growth factor 1 (IGF-1) are associated with increased risk of PCa and BC [9,10,11], multiple lines of evidence have shown that activation of the PI3K/ AKT/mTOR pathway, through insulin/IGF-1 stimulation and/or high levels of essential amino acids, play a crucial role in maintaining the malignant phenotype, and its inhibition antagonizes growth and motility of a range of cancer cells in mouse models [12,13,14,15,16,17]
LuCap23.1-CR xenograft growth was strikingly reduced in the 7% than in the 20% protein diet group, resulting in a 70% (p< 0.001, 95% CI= 55.98 to 139.7) reduced tumor size at 5 weeks post tumor implantation
Summary
Androgen-sensitive and castrate-resistant LuCaP23.1 xenograft models of human prostate cancer. Six-weeks old, male homozygous Icr SCID mice were purchased from the in-house animal resource core facility Roswell Park Cancer Institute (Buffalo, NY). Mice were housed and maintained in a sterile and pathogen free facility, in accordance with the Institutional guidelines credited by the Institutional Animal Care and Use Committee. Castrate-resistant (CR) LuCaP23.1 xenografts were generated by serial passages of androgensensitive (AS) LuCaP23.1 tumors in surgically-castrated mice [18]. LuCaP23.1 AS and CR tumors were dissected into ~1 mm pieces and implanted either subcutaneously www.impactjournals.com/oncotarget. 20% 10% dairy dairy protein protein Diet composition. Carbohydrate (%Kcal) 58.9 Fat (%kcal) Protein (%Kcal)
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