ROLE OF LIPOXYGENASES IN BREAST CANCER

Rama Natarajan and Jerry Nadler

Department of Diabetes, Endocrinology and Metabolism¹, City of Hope National Medical Center, 1500, E. Duarte Road, Duarte, California 91010, USA.

Received 5/15/98 Accepted 5/29/98

5. ACTIONS OF LIPOXYGENASE PRODUCTS RELATED TO CELL GROWTH AND ADHESION.

Lipoxygenase products such as the hydroxyeicosatetraenoic acids (HETEs) have been shown to have actions highly relevant to cellular growth and migration (18). They have significant mitogenic and chemotactic properties and can also stimulate the expression of several oncogenes (26-29). The 12-LO product, 12-hydroxyeicosatetraenoic acid (12(S)-HETE) has been shown to play a role in the growth promoting effects of angiotensin II in vascular smooth muscle and adrenal cells (30,31) and the chemotactic effects of platelet-derived growth factor (24). The LO products of linoleic acid can also potentiate the mitogenic effects of epidermal growth factor (EGF) (32,33) and linoleic acid can stimulate the growth of MCF-7 breast cancer cells (34,35). Linoleic acid metabolism enhances the proliferative response in mouse mammary epithelial cells and in human breast epithelial cells (36-38). The direct growth effects of linoleic acid , however, seemed more visible with the ER negative cell line MDA-MB-231 than with the ER positive MCF-7 cells (34). LO products rather than cyclooxygenase products were found to play a major role in linoleic acid-stimulated growth of mouse mammary tumor cell line (38).

The 12-LO product 12(S)-HETE, has been shown to play an important role in mediating several major steps of the process of hematogenous metastasis of cancer cells (39,40). 12(S)-HETE could mediate the adhesion of tumor cells to the subendothelial matrix following endothelial retraction by a protein kinase C- dependent process (40,41). 12-HETE was also shown to increase tumor cell motility and invasive potential (39,40). LO products such as 12- and 15-HETE also have angiogenic and mitogenic effects on endothelial cells (26). Liu et al. demonstrated that 12-HETE was the predominant arachidonic acid metabolite produced by highly metastatic tumor cells. Furthermore, these highly metastatic cells synthesized much greater amounts of 12-HETE than the low metastatic tumor cells, suggesting that biosynthesis of 12-HETE by tumor cells is a determinant of their metastatic potential (42). Evidence shows that arachidonic acid metabolism by lipoxygenase plays a key role in the adhesion of MDA-MB-435 breast cancer cells to collagen IV (43). Furthermore, platelet 12-lipoxygenase transfected MCF-7 breast cancer cells exhibited enhanced growth in athymic nude mice (44). The involvement of arachidonate LOs, particularly 12-LO, in the inhibition of apoptosis was demonstrated by Tang et al (45). This suggests that an increased concentration of 12-HETE produced by activated platelets, the tumor cells themselves, leukocytes or by vascular cells could facilitate the proliferative, adhesive and metastatic processes. Thus, a growing body of evidence suggests that specific metabolites of arachidonic and/or linoleic acid serve as central elements in signal pathways necessary for cell mitogenesis as induced by growth factors or oncogenic transformation.

However, very few studies have examined the cellular and molecular regulation of the LO enzymes in human breast cancer tissues and cells. We recently examined whether the leukocyte-type 12-LO expression is upregulated in breast cancer cells and tissue sections and also whether EGF, a breast cell growth factor, can induce LO activity and expression in breast cancer cells (46).