Oleate activates phosphatidylinositol 3-kinase and promotes proliferation and reduces apoptosis of MDA-MB-231 breast cancer cells, whereas palmitate has opposite effects

Epidemiological studies and experiments using animal models and cultured br east cancer cells have suggested that a high intake of dietary Fat could in crease breast cancer risk. Little Is known about the biochemical pathways b y which various free fatty acids (FFAs) influence breast cancer cell prolif eration and apoptosis, The present study was designed to investigate the ef fects of the two most abundant circulating FFAs, oleate and palmitate, on e stablished human breast cancer cell Lines after a short period of serum sta rvation. The unsaturated FFA oleate (C:18:1) stimulated cell proliferation, whereas the saturated FFA palmitate (C:16) dose dependently inhibited it. The half maximal effective concentrations of oleate and palmitate in the pr esence of albumin were 5 and 25 muM, respectively. The growth-inhibitory ef fect of palmitate in MDA-MB-231 cells was related to the induction of apopt osis as indicated by morphological and biochemical criteria. Moreover, olea te protected cells against the proapoptotic action of palmitate, Oleate and palmitate increased and decreased phophatidylinositol 3-kinase (PI3-K) act ivity, respectively, and the actions of the two FFAs on the enzyme were ant agonistic. The PU-K inhibitors wortmannin and LY294002 completely blocked t he proliferative action of oleate, 2-Bromopalmitate, a nonmetabolizable ana logue, did not affect MDA-MB-WI cell proliferation, suggesting that palmita te must be metabolized to exert its effect. Thus, various types of fatty ac ids are not equivalent with respect to their actions on breast cancer cell proliferation and apoptosis, The results support the concept that PU-K is i mplicated in the control of breast cancer cell growth by FFAs and that PI3- K may provide a link between fat and cancer. The data are also consistent w ith the view that the type of FFA and their ratios in the diet in addition to the total amount of fat influence mammary carcinogenesis.