Progesterone Increases Tissue Factor Gene Expression, Procoagulant Activity, and Invasion in the Breast Cancer Cell Line ZR-75-1

• Published in: The journal of clinical endocrinology and metabolism Vol. 90; no. 2; pp. 1181 - 1188
• Main Authors: Kato, Sumie, Pinto, Mauricio, Carvajal, Andrés, Espinoza, Natalia, Monso, Carolina, Sadarangani, Anil, Villalon, Manuel, Brosens, Jan J, White, John O, Richer, Jennifer K, Horwitz, Kathryn B, Owen, Gareth I
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Endocrine Society 01.02.2005; Copyright by The Endocrine Society
• Subjects: Biological and medical sciences; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cell Line, Tumor; Cell Survival; Endocrinopathies; Endometrial Neoplasms; Epidermal Growth Factor - pharmacology; Female; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Neoplastic - drug effects; Humans; Medical sciences; Neoplasm Invasiveness; Progesterone - pharmacology; Reverse Transcriptase Polymerase Chain Reaction; Sucrose; Thromboplastin - genetics; Thromboplastin - isolation & purification; Vertebrates: endocrinology; Tissue factor; Procoagulant activity; Breast cancer; Malignant tumor; Gene expression; Ovarian hormone; Invasion; Progestagen; Mammary gland diseases; Cell line; Established cell line; Progesterone; Sex steroid hormone; Tumor cell; Endocrinology
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2004-0857

Progesterone in hormonal preparations increases the incidence of breast cancer. Tissue factor (TF), the initiator of the extrinsic coagulation pathway, is associated with metastasis in a wide variety of cancers. We demonstrate herein that TF mRNA and protein are up-regulated by progesterone in the breast cancer cell line ZR-75. Epidermal growth factor, also associated with increased breast cancer risk, did not regulate TF. The increase in TF is both rapid and transient; increasing after 6 h, reaching a maximum at 24 h, before decreasing to basal levels at 72 h. Sucrose gradient experiments demonstrated that TF is located in the heavy fraction of the plasma membrane, although caveolin-1 is not expressed in ZR-75. To understand the physiological implications of an increase in TF, we performed coagulation and invasion assays. An increase in TF corresponded to an increase in procoagulant activity. Furthermore, progesterone increased the invasion of ZR-75 cells through a matrigel, an effect that was blocked by an antibody against TF. Because TF expression is associated with an enhanced risk of metastasis, we postulate that the progesterone-dependent up-regulation of TF provides a survival advantage to burgeoning breast cancer cells and may contribute to the increased risk of cancer associated with combined hormone replacement therapy.