Dietary Flaxseed–Trastuzumab Interactive Effects on the Growth of HER2-Overexpressing Human Breast Tumors (BT-474)

Abstract

Flaxseed (FS) reduces breast tumorigenesis and human epidermal growth factor receptor 2 (HER2) expression in postmenopausal patients and animal models. The primary treatment for HER2-overexpressing tumors is trastuzumab (TRAS). FS oil enhances TRAS effectiveness in athymic mice but the FS effect is unknown and was therefore determined. Athymic mice with established BT-474 tumors were fed the basal diet (control), or 10% FS diet, with or without TRAS (2.5mg/kg) treatment for 5 wk. After 2 wk, TRAS and FS reduced tumor size with a trend for an FS × TRAS interaction; however, after 5 wk, only TRAS reduced tumor size and increased tumor apoptosis. FS did not further improve TRAS effect but increased overall survival. TRAS reduced signaling biomarkers [phosphorylated HER2 and mitogen-activated protein kinase (MAPK) proteins; Akt1, Akt2, MAPK, and estrogen receptor-α mRNA], FS reduced phosphorylated-Akt1 protein, and FS × TRAS interactions were seen for HER2 mRNA and phosphorylated-Akt1 protein. FS, with and without TRAS, increased tumor n-3 PUFA levels and serum lignans indicating potential roles in the observed effect. In conclusion, TRAS reduces tumor growth by influencing HER2 signaling. Dietary FS has minimal tumor-reducing effect, does not interfere with TRAS action, but improves overall survival in athymic mice.

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

“…In the case of the RAS/ERK pathway, these therapeutic agents mainly consist of inhibitors of the upstream GR Receptors (GFR, such as EGFR or HER/neu), RAF or MEK1/2 [44], and in the case of the phosphoinositide cascade, principally consist of inhibitors of GFR, as well as of PI3K. Recently, for their known antineoplastic properties and their ability to powerfully modulate both these signaling pathways in breast cancer, the potential of LCn-3 PUFA to function as adjuvants in combination with Trastuzumab has been investigated in in vitro and in preclinical models [26,45,46]. Trastuzumab is a specific inhibitor of the overexpressed receptor tyrosine kinase HER2/neu placed upstream of the activation of the Ras/ERK pathway [47].…”

“…Recent studies performed in vivo by Mason et al have yielded interesting suggestions regarding the potential adjuvant role of LCn-3 PUFA in HER2/neu positive breast cancer [45,46]. The authors injected BT-474 cells into nude mice fed with a diet enriched with 4% Flaxseed oil (FSO) for four weeks, and combined this diet with Trastuzumab, an antibody specifically directed against the overexpressed HER2/neu receptor, and currently used in the therapy of human breast cancer positive for this receptor.…”

“…The FSO used by these authors contained 57% of α-linolenic acid (ALA, 18:3n-3), which is the metabolic precursor of DHA, but is not efficiently converted into DHA in mammalian cells. Indeed, Mason et al [46] found that the FSO diet increased ALA levels in BT-474 tumors by about eight times, but the levels of DHA were less than doubled [46]. In this case, dietary FSO increased the suppressing effect of Trastuzumab on tumor growth by interacting with Trastuzumab to suppress p-HER2, p-ERK-2, and p-AKT1 expression [46].…”

“…Indeed, Mason et al [46] found that the FSO diet increased ALA levels in BT-474 tumors by about eight times, but the levels of DHA were less than doubled [46]. In this case, dietary FSO increased the suppressing effect of Trastuzumab on tumor growth by interacting with Trastuzumab to suppress p-HER2, p-ERK-2, and p-AKT1 expression [46]. However, as reported above, in their most recent in vitro work, Mason et al [26] found that, whereas DHA was able to increase the suppressive action of Trastuzumab on p-ERK and p-Akt expression, such a potentiating effect was not found when they tested ALA.…”

The Role of n-3 Polyunsaturated Fatty Acids in the Prevention and Treatment of Breast Cancer

“…Moreover, ALA co-exposure was reported to synergistically enhance trastuzumab (an anti-cancer therapy) efficacy in HER2-overexpression BC cells [ 139 ]. However, in a separate study, ALA exerted minimal tumor-reducing effects in the presence of trastuzumab [ 140 ]. In addition, some studies had difficulties in characterizing the role of ALA in estrogen dependent and independent BC cell lines [ 122 , 124 ].…”