Proliferation Of Estrogen-dependent Cancer Cells Research Articles

Peroxisome Proliferator-Activated Receptor as a Therapeutic Target in Human Breast Cancer

Objective: Peroxisome proliferator-activated receptor γ (PPARγ) is aberrantly expressed in most breast tumors, suggesting the potential of agents that target this receptor in treatment and chemoprevention of breast cancer. However, whether PPARγ leads to the promotion or reduction of tumor formation has remained controversial and is further complicated by the ability of its available thiazolidinedione (TZD) ligands to activate another PPAR subtype, PPARδ. Method: To examine the role of each receptor in breast cancer biology, we performed a systematic evaluation of PPARγ and PPARδ agonists on the growth of human estrogen receptor (ER)-positive and -negative breast cancer cells. Results: In this manner we found that TZD-activated PPARγ was highly effective in suppressing the proliferation of estrogen-dependent cancer cells. Activated PPARδ, however, displayed growth-enhancing effects independent of estradiol and regardless of the ER status of the cells. Strikingly, in ER-negative cancer cells expressing a favorable PPARδ/γ ratio, TZDs promoted growth in a PPAR γ-independent manner by direct activation of PPARδ. A screen for ligands with increased receptor selectivity compared to TZDs revealed that GW7845 functioned as a full agonist of PPARγ, yet this agent lacked the ability to activate PPARδ and elicit its associated mitogenic effects. Conclusion: These studies indicate that selective PPAR γ modulators (SPPARγMs) that lack agonist activity on PPARδ may be clinically useful in future cancer treatment and chemoprevention.

Abstract 1706: Estrogen induces stearoyl-CoA desaturase expression in human MCF-7 breast carcinoma cells.

Abstract Approximately 95% of breast cancers are estrogen-dependant. Estrogen plays a crucial role in many cellular processes in estrogen-sensitive breast cancer such as carcinogenesis, production of growth factors, angiogenesis and growth stimulation. To sustain cell growth, many cancer cells exhibit an altered metabolism that is characterized by increased glycolysis and lipogenesis. We observed for the first time an up regulation of stearoyl-CoA desaturase-1 (SCD1) in response to estrogen in the hormone-dependent MCF7 human breast carcinoma cell line. SCD1 is a key enzyme in the production of monounsaturated fatty acids that are essential for membrane biogenesis. Using estrogen-starved MCF7 cells, treatment with 2 nM of estrogen induced cell proliferation, increased SCD-1 gene expression measured by qPCR (2.6±0.1 fold increase, p<0.05) and SCD-1 protein expression (7.2 fold increase) determined by immunoblot analysis, compared to control cells. Estrogen-induced SCD1 expression was accompanied by important changes in cellular fatty acid compositions with significant increases in the monounsaturated fatty acid content in membrane phospholipids and in SCD-1 product/substrate ratios with a 4.3±0.03 fold increase in the 16:1n-7/16:0 ratio and a 1.9±0.01 fold increase in the 18:1n-9/18:0 ratio compared to untreated cells (both p<0.05). Treatment of estrogen-stimulated cells with a selective SCD1 inhibitor inhibited estrogen-induced cell proliferation and prevented the estrogen-induced changes in membrane lipid composition. Overall, these results show for the first time that estrogen induces SCD-1 expression in breast carcinoma cells and suggests a crucial role for SCD1 in estrogen dependent cancer cell proliferation. SCD1 may therefore represent a potential therapeutic target for estrogen-dependent cancer. (This work was supported by the Canadian Institutes of Health Research and the Canada Research Chairs Program). Citation Format: Anissa Belkaid, Rodney J. Ouellette, Marc E. Surette. Estrogen induces stearoyl-CoA desaturase expression in human MCF-7 breast carcinoma cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1706. doi:10.1158/1538-7445.AM2013-1706