title: Progestin modulates the lipid profile and sensitivity of breast cancer cells to docetaxel.
abstract: Progestins induce lipid accumulation in progesterone receptor (PR)-positive breast cancer cells. We speculated that progestin-induced alterations in lipid biology confer resistance to chemotherapy. To examine the biology of lipid loaded breast cancer cells, we used a model of progestin-induced lipid synthesis. T47D (PR-positive) and MDA-MB-231 (PR-negative) cell lines were used to study progestin response. Oil red O staining of T47D cells treated with progestin showed lipid droplet formation was PR dependent, glucose dependent and reduced sensitivity to docetaxel. This protection was not observed in PR-negative MDA-MB-231 cells. Progestin treatment induced stearoyl CoA desaturase-1 (SCD-1) enzyme expression and chemical inhibition of SCD-1 diminished lipid droplets and cell viability, suggesting the importance of lipid stores in cancer cell survival. Gas chromatography/mass spectroscopy analysis of phospholipids from progestin-treated T47D cells revealed an increase in unsaturated fatty acids, with oleic acid as most abundant. Cells surviving docetaxel treatment also contained more oleic acid in phospholipids, suggesting altered membrane fluidity as a potential mechanism of chemoresistance mediated in part by SCD-1. Lastly, intact docetaxel molecules were present within progestin induced lipid droplets, suggesting a protective quenching effect of intracellular lipid droplets. Our studies suggest the metabolic adaptations produced by progestin provide novel metabolic targets for future combinatorial therapies for progestin-responsive breast cancers.
authors.affiliation: Department of Medicine, Division of Endocrinology, Metabolism, and Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Isabel R
authors.initials: IR
authors.lastname: Schlaepfer
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Hitz
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Gijón
authors.forename: Bryan C
authors.initials: BC
authors.lastname: Bergman
authors.forename: Robert H
authors.initials: RH
authors.lastname: Eckel
authors.forename: Britta M
authors.initials: BM
authors.lastname: Jacobsen
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D005947:Glucose / Q000378:metabolism / Q000502:physiology; D006067:Gonanes / Q000494:pharmacology; D006801:Humans; D050155:Lipogenesis / Q000187:drug effects*; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology*; D010743:Phospholipids / Q000378:metabolism; D011372:Progestins / Q000494:pharmacology*; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors / Q000378:metabolism; D013230:Stearoyl-CoA Desaturase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D043823:Taxoids / Q000378:metabolism / Q000494:pharmacology*; D014280:Triglycerides / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D005230:Fatty Acids, Nonesterified; D006067:Gonanes; D010743:Phospholipids; D011372:Progestins; D011980:Receptors, Progesterone; D043823:Taxoids; D014280:Triglycerides; D000077143:Docetaxel; D017258:Medroxyprogesterone Acetate; C523776:SCD1 protein, human; D013230:Stearoyl-CoA Desaturase; C053238:onapristone; D005947:Glucose