Modulation of Ras/ERK and Phosphoinositide Signaling by Long-Chain n-3 PUFA in Breast Cancer and Their Potential Complementary Role in Combination with Targeted Drugs.

Simona Serini,Gabriella Calviello

doi:10.3390/nu9030185

Simona Serini, Gabriella Calviello

Open Access

https://doi.org/10.3390/nu9030185

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Journal: Nutrients	Publication Date: Feb 23, 2017
Citations: 29	License type: CC BY 4.0

Affiliation: Università Cattolica del Sacro Cuore

Abstract

A potential complementary role of the dietary long-chain n-3 polyunsaturated fatty acids (LCn-3 PUFA) in combination with innovative mono-targeted therapies has recently been proposed. These compounds are thought to act pleiotropically to prevent the development and progression of a variety of cancers, including breast cancer. We hereinafter critically analyze the reports investigating the ability of LCn-3 PUFA to modulate the Ras/ERK and the phosphoinositide survival signaling pathways often aberrantly activated in breast cancer and representing the main targets of innovative therapies. The in vitro or in vivo animal and human interventional studies published up to January 2017 investigating the effects of LCn-3 PUFA on these pathways in normal and cancerous breast cells or tissues were identified through a systematic search of literature in the PubMed database. We found that, in most cases, both the in vitro and in vivo studies demonstrated the ability of LCn-3 PUFA to inhibit the activation of these pro-survival pathways. Altogether, the analyzed results strongly suggest a potential role of LCn-3 PUFA as complementary agents in combination with mono-targeted therapies. Moreover, the results indicate the need for further in vitro and human interventional studies designed to unequivocally prove the potential adjuvant role of these fatty acids.

Highlights

Several in vitro and in vivo experimental studies have supported the antineoplastic role of the long-chain n-3 polyunsaturated fatty acids (LCn-3 PUFA) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), present at high levels in fatty fish
In agreement with the above analyzed studies, Sun et al [68] showed that the phosphorylation of MEK and ERK was lower in the fat-1 transgenic mouse mammary tissue than in wild-type tissue. They found that BAD was less phosphorylated, and able to positively regulate apoptosis [68]. These results suggest that, in normal mammary tissue, the LCn-3 PUFA, through their ability to maintain the ERK1/2 and PI3K/Akt/mammalian target of rapamycin (mTOR) at low level of activities, could have the potential to exert a preventive action against the risk of breast cancer, comparable to that of selective estrogen receptor modulators, approved for breast cancer prevention (Tamoxifen and Raloxifene)
These findings are of great practical importance and deserve great attention, Manni et al [92,93] had previously observed that an FO diet rich in LCn‐3 PUFA enhanced the since Manni et al [92,93] had previously observed that an FO diet rich in LCn-3 PUFA enhanced the chemopreventive effects of Tamoxifen on MNU‐induced rat mammary carcinogenesis by inhibiting chemopreventive effects of Tamoxifen on MNU-induced rat mammary carcinogenesis by inhibiting the development of preneoplastic lesions, as well as the regression of those already established

Summary

Introduction

Several in vitro and in vivo experimental studies have supported the antineoplastic role of the long-chain n-3 polyunsaturated fatty acids (LCn-3 PUFA) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), present at high levels in fatty fish. One remarkable feature of these dietary compounds and their metabolic derivatives is the ability to act pleiotropically to prevent the development and progression of cancer [1,2] They have been shown to reduce inflammation and induce its resolution [3], as well as to foster apoptosis [4] and differentiation [5] in cancer cells. Multiple components of molecular pathways involved in these processes are known to be targets of LCn-3 PUFA action that can significantly affect their expression and/or activity [7] Among these targets are membrane receptors, protein kinases and phosphatases [8,9], transcription factors, cyclins, and components or modulators of the apoptotic and autophagic pathways [10]. Multiple and often unrelated, their effects at Nutrients 2017, 9, 185; doi:10.3390/nu9030185 www.mdpi.com/journal/nutrients

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