Journal of Steroid Biochemistry & Molecular Biology 115 (2009) 153–160 Contents lists available at ScienceDirect Journal of Steroid Biochemistry and Molecular Biology journal homepage: www.elsevier.com/locate/jsbmb Progestins induce catalase activities in breast cancer cells through PRB isoform: Correlation with cell growth inhibition Emile Petit a,1 , Aurélie Courtin a,1 , Helenius J. Kloosterboer b , William Rostène c , Patricia Forgez a , Anne Gompel a,d,∗ a INSERM-UPMC Univ Paris 06, UMRS 938, Hôpital Saint-Antoine, Paris, France b Organon, Part of Schering-Plough Oss, The Netherlands c INSERM-UPMC U732 Hôpital Saint-Antoine, Paris, France d UF de Gynécologie, AP-HP, Hôtel-Dieu, Université Paris Descartes, Paris, France article info Article history: Received 7 December 2008 Received in revised form 7 April 2009 Accepted 8 April 2009 Keywords: Progesterone Tibolone MPA NETA Hydrogen peroxide Normal breast cells abstract Reactive oxygen species (ROS) have been suggested to participate in tumor emergence due to their mitogenic and apoptotic signaling, and as contributors to DNA structural damage. Here we report that progesterone and various synthetic steroids with progestin potencies (norethisterone acetate, MPA, and Tibolone) counteract cell growth induced by hydrogen peroxide (H 2 O 2 ), through a potent induction of catalase activities, in breast cancer cells and normal human epithelial breast cells. At physiological con- centrations, progesterone and the pure progestin, Org2058, displayed the most potent H 2 O 2 detoxification ability suggesting its effect was characteristic of its progestin potency. We also report on the enhancement of catalase activities by progesterone receptor isoform B (PRB), as determined from experiments using antiprogestins and MDA-MB-231, cells engineered for the selective expression of progesterone receptor isoform A or B. The potent action of progesterone on catalase activities indicates its contribution to a beneficial role in breast cell homeostasis. © 2009 Elsevier Ltd. All rights reserved. 1. Introduction ROS are known to severely affect cellular proliferation and apoptosis regulation [1,2]. ROS include multiple molecular species (H 2 O 2 , peroxides, hydroxyl radicals, nitric oxide) and are continu- ously generated in mammalian cells as a consequence of aerobic respiration. The initiation of ROS generation occurs through the reduction of oxygen to produce superoxides (O 2 - ). Superoxides can spontaneously dismutate into H 2 O 2 or under the control of superoxide dismutase (SOD). The main step in H 2 O 2 cellular detoxification relies upon catalase activities, where these enzymes transform H 2 O 2 into H 2 O and O 2 . ROS are also involved in growth factor transduction pathways through the alteration of protein- tyrosine phosphorylation, and modulate the function of specific proteins involved in apoptosis, such as p53, and caspases [3,4]. The external addition of low concentrations of H 2 O 2 and/or O 2 - were shown to promote cell growth in various cell types (fibrob- lasts, smooth muscle cells, aortic endothelial cells) [5,6] whereas over expression of catalase or SOD inhibits cell proliferation and cell ∗ Corresponding author at: UF de Gynécologie, Hôtel-Dieu, 1 Place du Parvis Notre-Dame, Paris 75004, France. Fax: +33 143298766. E-mail address: anne.gompel@htd.aphp.fr (A. Gompel). 1 These authors have equally contributed to the work. death [6,7]. ROS are involved in tumorigenesis initiation and pro- gression caused by the disruption of these pathways and its direct DNA toxicity [8,9]. A number of studies concerning ROS concentration and their catabolism indicate a direct role of ROS in breast cancer progres- sion. Large quantities of hydrogen peroxide (H 2 O 2 ) are released, most likely derived from superoxide, in breast cancer cells [10]. Serum markers for oxidative DNA damage were shown to increase in women diagnosed with breast cancer [9]. More recently, the detoxification pathway, particularly catalase expression and activa- tion, was associated with the control of breast cancer progression. For example, acatalasemic and hypocatalasemic mice, which have drastically decreased catalase levels in the blood and tissues, are more susceptible to mammary carcinoma than their wild type counterparts [11]. In humans, a C/T polymorphism at base pair 262 was identified in the promoter region of the catalase gene (CAT) with higher catalase activities with the CC genotype. The authors observed that the CC allele was linked with an overall 17% reduc- tion in risk of breast cancer as compared to its T variant. This effect was even more pronounced in women with high consumption of fruits and vegetables [12]. Another recent publication, showed an increased risk related to HRT use in women with the CT or TT CAT genotypes [13]. In addition, estradiol decreases catalase activ- ities involved in the antioxidant effects in breast cancer cells. This effect was mediated by the estradiol receptor alpha, suggesting that 0960-0760/$ – see front matter © 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.jsbmb.2009.04.002