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Dysregulation of fatty acid metabolism is recognized as a component of malignant transformation in many different cancers, including breast; yet the potential for targeting this pathway for prevention and/or treatment of cancer remains unrealized. Evidence indicates that proteins involved in both synthesis and oxidation of fatty acids play a pivotal role in the proliferation, migration and invasion of breast cancer cells. The following essay summarizes data implicating specific fatty acid metabolic enzymes in the genesis and progression of breast cancer, and further categorizes the relevance of specific metabolic pathways to individual intrinsic molecular subtypes of breast cancer. Based on mRNA expression data, the less aggressive luminal subtypes appear to rely on a balance between de novo fatty acid synthesis and oxidation as sources for both biomass and energy requirements, while basal-like, receptor negative subtypes overexpress genes involved in the utilization of exogenous fatty acids. With these differences in mind, treatments may need to be tailored to individual subtypes.

The mechanisms of steroid and peptide hormone action in human breast cancer are poorly understood. We have previously characterized a cell line of human breast cancer in long-term tissue culture that possesses various steroid hormone receptors and responses, providing a model for the study of steroid hormone action. The present studies describe a human breast cancer in vitro that responds to physiologic concentrations of insulin with an increased rate of macromolecular synthesis and growth. Thymidine and uridine incorporation in cells in serum-free medium are stimulated by 10-11 M insulin and are maximal with 10-8 M. Leucine incorporation is stimulated by 5 X 10-11 M insulin and is maximal with 10-9 M. Significant stimulation of uridine and leucine incorporation is evident by 3 hr and maximal by 10 hr. A 10-hr lag period exists for insulin stimulation of thymidine incorporation, which is maximal from 14 to 24 hr. The effect of 10-8 M insulin on macromolecular synthesis is accompanied by a 69% increase above controls in the number of cells after 24 hr. The effect on macromolecular synthesis is observed in glucose-free medium. Insulin's effect on protein synthesis is not blocked by inhibition of RNA synthesis with actinomycin D. Glucocorticoids partially inhibit the action of insulin in these cells. This system provides a model for studying insulin action, and suggests that some human breast cancer may show growth regulation by insulin. We have recently characterized a model system for the study of steroid hormone action using human breast cancer cells maintained in long-term tissue culture (1, 2). One cell line in particular, MCF-7, possesses specific high affinity receptors for estradiol, progesterone, androgens, and glucocorticoids (1-4). In addition, these cells respond to estrogen and androgen with an increased rate of DNA, RNA, and protein synthesis, while inhibition of macromolecular synthesis is observed with glucocorticoids and the antiestrogen, Tamoxifen (ICI 46474) (1-3).The effect of peptide hormones on these cells is unknown. However, insulin is known to influence mammary gland growth and development in human (5) and rodent glands in organ culture (6), and other studies suggest that insulin regulates proliferation of rat mammary carcinomata induced by the carcinogen dimethylbenz[a]anthracene (7,8).In the present study we demonstrate that the MCF-7 cell line is responsive to physiologic concentrations of insulin and propose that this cell line provides a provocative model for the study of insulin action and mechanisms of growth regulation in breast cancer. Cells and Tissue Culture Techniques. The MCF-7 cell line, a cloned breast cancer line derived from a malignant pleural effusion (9), was generously provided by Dr. Marvin Rich, Michigan Cancer Foundation. The human and mammary nature of this line has been substantiated by chromosomal analysis, morphological features, and a-lactalbumin synthesis (10). The cells (at approximately the 100th passage) were maintained in monolayer cultures in Impro...

Previous studies have shown that key enzymes involved in lipid metabolic pathways are differentially expressed in normal compared with tumor tissues. However, the precise role played by dysregulated expression of lipid metabolic enzymes and altered lipid homeostasis in carcinogenesis remains to be established. Fatty acid synthase is overexpressed in a variety of cancers, including breast and prostate. The purpose of the present study was to examine the expression patterns of additional lipid metabolic enzymes in human breast and prostate cancers. This was accomplished by analysis of published expression databases, with confirmation by immunoblot assays. Our results indicate that the fatty acid-activating enzyme, long-chain fatty acyl-CoA synthetase 4 (ACSL4), is differentially expressed in human breast cancer as a function of estrogen receptor alpha (ER) status. In 10 separate studies, ACSL4 messenger RNA (mRNA) was overexpressed in ER-negative breast tumors. Of 50 breast cancer cell lines examined, 17 (89%) of 19 ER-positive lines were negative for ACSL4 mRNA expression and 20 (65%) of 31 ER-negative lines expressed ACSL4 mRNA. The inverse relationship between ER expression and ACSL4 expression was also observed for androgen receptor status in both breast and prostate cancers. Furthermore, loss of steroid hormone sensitivity, such as that observed in Raf1-transfected MCF-7 cells and LNCaP-AI cells, was associated with induction of ACSL4 expression. Ablation of ACSL4 expression inMDA-MB-231 breast cancer cells had no effect on cell proliferation; however, sensitivity to the cytotoxic effects of triacsin C was increased three-fold in the cells lacking ACSL4.