n-3 and n-6 PUFA-mediated modulation of HER-2/neu membrane localization and signaling in breast cancer

B69

Given the poor prognosis of HER-2/neu overexpression positive and/or hormone resistant breast cancer and reliance on toxic systemic therapies, new treatments to prevent the onset and/or recurrence of this aggressive molecular subtype are needed. We previously demonstrated that fish oil-based diets suppressed breast tumor incidence (p=0.0001), multiplicity (p=0.001), and mammary gland atypia (p=0,001) in HER-2/neu transgenic mice. These findings led us to hypothesize that HER-2/neu-mediated mammary carcinogenesis may be uniquely susceptible to dietary n-3 polyunsaturated fatty acids (PUFAs). To determine the effects of n-3 versus n-6 PUFAs on early pre-invasive stages of HER-2/neu-mediated mammary carcinogenesis, we fed HER-2/neu mice diets enriched with corn or fish oil (25% of energy) from 7 weeks to 25, 30 and 35 weeks of age. Although histopathologic assessment of mammary glands did not reveal significant differences in the grade of mammary gland atypia between the ages, the grade differed significantly between the diets (p = 0.0035), controlling for age. On average, the estimated grade for mice fed the corn oil diets was 1.43 times higher than mice fed the fish oil enriched diets (95% CI: 0.47, 2.39). In order to elucidate the potential mechanism of these effects on early HER-2/neu-induced carcinogenesis, we investigated the modulation of HER-2/neu receptor interactions in the cell membrane and subsequent modulation of downstream signal transduction. Treatment of HER-2/neu+ breast cancer cells with n-3 and n-6 PUFAs demonstrated displacement of HER-2/neu protein from the lipid raft compartment of the cell membrane, which correlated with downregulation of signaling through ras and Akt. Membrane localization of HER-3, a heterodimer partner for HER-2/neu, also decreased in the raft fractions. HER-2/neu expression also decreased with n-3 versus n-6 PUFA treatment, indicating that the inhibitory effects of n-3 fatty acids on HER-2/neu-mediated signaling may result from both downregulation of the receptor and disruption of membrane signaling complexes. Dietary n-3 PUFAs may thus target specific molecular subtypes of breast cancer such as HER-2/neu-mediated disease that rely on protein-membrane interactions.