a-Linolenic Acid Reduces Growth of Both Triple Negative and Luminal Breast Cancer Cells in High and Low Estrogen Environments

Key Findings:

Breast cancer (BC) growth and responsiveness to treatments are influenced by the estrogen level of the tumor microenvironment, and the BC molecular subtype based on expression of cell estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). The molecular subtypes consist of luminal A (ERC PR C HER2-), luminal B (ERC PRC HER2C), HER2 overexpressing (ER- PR- HER2C), and basal-like (ER- PR- HER2-), which many refer to as triple negative breast cancer (TNBC). In this study, ALA decreased BC cell growth in luminal A, luminal B, and TNBC cell lines, both with and without E2, effects that were associated with the level of incorporation of ALA in the phospholipids. ALA at lower doses (50 mM) significantly reduced the growth of MCF-7 and MDA-MB-231 cell lines, and the HER2 overexpressing BT-474 and TNBC MDA-MB- 468 cell lines. ALA has been shown to increase apoptosis in BC cells, a possible explanation for its growth inhibiting ability. ALA and ALA-rich foods are potential complementary dietary treatment options for BC regardless of tumor receptor expression and menopausal status and may be particularly effective in difficult to treat TNBC.

ABSTRACT:

Flaxseed, rich in a-linolenic acid (ALA), is a complementary breast cancer (BC) therapy; however ALA effectiveness and mechanism are unclear. Variation in cellular expression of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and estrogen (E2) levels may alter ALA effectiveness. This research determined the effect of ALA on growth, apoptosis, and phospholipid fatty acids of 4 BC cell lines with varying receptor expression § E2. MCF-7 (ERC/PRC/HER2-), BT-474 (ERC/PRC/HER2C), MDA-MB-231 (ER-/PR-/HER2-) and MDA-MB-468 (ER-/PR-/HER2-) cells were incubated with ALA (50–200 mM) § 1 nM E2 for 48–72 h. ALA dose-dependently reduced growth, measured by trypan blue exclusion, of all cells (55–80% with 75 mM), and this effect was not altered by E2. ALA (75 mM)+E2 induced apoptosis, measured by flow cytometry (up to 111.2%). Decreased growth and increased apoptosis is related to increased cell phospholipid % ALA (up to 25.1%), measured by gas chromatography. ALA is shown for the first time to reduce cell growth and induce apoptosis regardless of receptor expression and E2 environment, by incorporating into BC phospholipids, supporting the use of ALA and ALA-rich foods as a safe, inexpensive complementary therapy for a wide range of BC. (Authors abstract)