| Breast cancer is one of the leading causes of women's death in Canada. With 70% of breast tumors that are positive for estrogen receptor (ER), characterization and understanding of hormone-dependent tumor growth mechanisms remain relevant for improving patient care. Metabolic modification is a hallmark of tumor cells that use different metabolites to meet their growing needs in macromolecules. Unlike normal cells, the regulation of tumor cell metabolism is influenced by oncogenes and growth factors. A better understanding of these regulatory mechanisms can be promising for the identification of new therapeutic targets.;First, we compared the metabolism of MCF-7 breast carcinoma cells following treatment with the ER agonists estrogen and ferulic acid to that of normal MCF-10A mammary epithelial cells. We observed an increase in glucose consumption in MCF- 7 carcinoma cells compared to the immortalized MCF-10A mammary epithelial cells. Also the levels of lactate and various Krebs cycle metabolites were higher in cancer cells treated with estrogen as compared to the control conditions. The Krebs cycle metabolites, such as acetyl-CoA, are precursors for the biosynthesis of macromolecules, such as fatty acids, that are building blocks for the newly synthesised cellular membranes essential for tumor growth.;Following these results, we investigated fatty acid metabolism in breast carcinoma cells treated with estradiol, especially the effect of estradiol on the expression/activity of steroyl-CoA desaturase (SCD-1). SCD-1 is a desaturase responsible for the synthesis of monounsaturated fatty acids such as 16:1n-7 and 18:1n-9. We demonstrated that estradiol increases SCD-1 expression and activity required to promote new membrane synthesis to support tumor growth. Estradiol induced SCD-1 expression through the activation of SREBP-1, a transcription factor whose target genes include SCD-1.;The proper ratio of saturated/unsaturated fatty acids is important for the integrity of the cellular membranes. In the final part of this work, we evaluated the incorporation rate of polyunsaturated fatty acids arachidonic acid (AA) and eicosapentaenoic acid (EPA) into breast carcinomas cells and the enzymes that are responsible for this uptake. We observed that in estradiol-treated cells AA and EPA uptake were higher compared to non-treated cells. This was a consequence of an increase in acyl CoA synthetase-4 (ACSL4) expression. ACSL4 is an enzyme responsible for the synthesis of AA-CoA and EPA-CoA, the activated forms of AA and EPA. ACSL4's products seem important for the synthesis of new cellular membranes, but also the promotion of the invasive phenotype induced by estradiol in mammary carcinoma cells.;Overall, in this work we demonstrated that cells derived from breast carcinomas switch their metabolism to promote tumor growth. Specifically, we demonstrated that the poly- and mono-unsaturated fatty acids play important roles in supporting tumor growth influenced by estrogen. More than just membrane components, these fatty acids may be involved in complex processes associated with the phenotypic changes of tumor cells.;Key words: Breast cancer, estrogen receptor (ER), estradiol, steroyl-CoA desaturase-1 (SCD-1), acyl-CoA synthetase-4 (ACSL4), steroid response element binding protein-1 (SREBP-1). |
