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New Insight on a Possible Mechanism of Progestogens in Terms of Breast Cancer Risk

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New Insight on a Possible Mechanism of Progestogens in Terms of Breast Cancer Risk Article in press - uncorrected proof Horm Mol Biol Clin Invest 2011;6(1):185–192 ᮊ 2011 by Walter de Gruyter • Berlin • New York. DOI 10.1515/HMBCI.2010.082 New insight on a possible mechanism of progestogens in terms of breast cancer risk Hans Neubauer1,a, Rong Chen2,a, Helen Schneck1, gestins that are used for hormone therapy are different in Thomas Knorrp3, Markus F. Templin3, Tanja Fehm1, their proliferative effects on MCF-7 and MCF-7/PGRMC1- Michael A. Cahill4, Harald Seeger1,QiYu2 and 3HA cells. Progesterone appears to act neutrally, whereas Alfred O. Mueck1,* MPA, NET and DRSP trigger proliferation and thus might increase breast cancer risk. The data presented are very 1Department of Obstetrics and Gynecology, University of important in terms of the positive results of progestogens and Tuebingen, Tuebingen, Germany breast cancer risk in clinical studies so far. 2Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Beijing, China Keywords: progestogens; progesterone receptor membrane 3Natural and Medical Sciences Institute at the University component 1; proliferation; signal cascade. of Tuebingen, Reutlingen, Germany 4School of Biomedical Sciences, Charles Sturt University, Wagga Wagga, NSW, Australia Introduction Abstract Hormone therapy and oral contraception are still an impor- Objectives: Progestogens influence mammary gland devel- tant risk factor for breast cancer. Evidence is accumulating opment and probably breast cancer tumorigenesis by regu- that progestogens can play a crucial role. Progesterone recep- lating a broad spectrum of physiological processes. We tor membrane component 1 (PGRMC1) is expressed in investigated receptor membrane-initiated actions of proges- breast cancer w1, 2x. It could be important in tumorigenesis togens in MCF-7 breast cancer cells overexpressing proges- and thus could increase breast cancer risk. Little is known terone receptor membrane component 1 (PGRMC1). about downstream signaling pathways w3, 4x. Design: MCF-7 cells were stably transfected with PGRMC1 The role of progestogen addition to estrogen therapy in expression plasmid (MCF-7/PGRMC1-3HA) and overex- postmenopause has come under scrutiny since the results of pression of PGRMC1 was verified by immune fluorescent the Women’s Health Initiative (WHI) mono arm were pub- analysis and Western blot. To test the effects of progestogens lished compared to the WHI combined arm w5, 6x. The WHI on cell proliferation, MCF-7 and MCF-7/PGRMC1-3HA trial used the combination of conjugated equine estrogens cells were stimulated with a membrane-impermeable proges- plus medroxyprogesterone acetate (MPA). In contrast to the terone: BSA-fluorescein-isothiocyanate conjugate (P4-BSA- WHI combined arm, in the estrogen only arm no increase FITC), unconjugated progesterone (P4), medroxyproges- but rather a reduction of breast cancer risk was found, which terone acetate (MPA), norethisterone (NET) and drospire- was significant for patients with more than 80% adherence none (DRSP). Furthermore, reverse phase protein technology to study medication w7x. This result indicates a negative was applied to identify modified downstream signaling. effect of progestogens with regard to breast cancer risk. Results: Progesterone did not elicit any proliferative effect However, it remains unclear whether the combination of on MCF-7/PGRMC1-3HA cells. By contrast, P4-BSA-FITC, estrogens with synthetic progestins and/or natural progester- DRSP, MPA and NET significantly triggered proliferation one can elicit the same increased risk. Thus, many questions of MCF-7/PGRMC1-3HA cells, the effect being more pro- concerning the extrapolation of the WHI results to all syn- nounced for NET. Almost no effect of progestogens on thetic progestogens and to natural progesterone remain proliferation was observed in MCF-7 cells. In MCF-7/ unanswered. Of special note is one cohort study using PGRMC1-3HA cells, expression of Erk1/2 was significantly micronized progesterone in combination with estrogens, reduced by 40% compared to MCF-7 cells. which detected no increase in breast cancer risk when com- Conclusions: Our data indicate that PGRMC1 mediates a bining transdermal (patches) or percutaneous (gels) estradiol progestogen-dependent proliferative signal in MCF-7 cells. therapy with progesterone w8x. In 80,377 women breast can- Of significant interest is that progesterone and synthetic pro- cer risk was increased with oral synthetic progestogens, but not with progesterone and dydrogesterone. The mean dura- a These authors contributed equally. tion of hormone therapy (HT) was 7 years. This study had *Corresponding author: Professor Alfred O. Mueck, MD, a mean follow-up of 8.1 years. PharmD, PhD, University Women’s Hospital, Department of Progestogens are conventionally thought to act via the Endocrinology and Menopause, Head, Center of Women’s Health activation of the intracellularly located progesterone recep- BW, Head, Calwer Strasse 7, D-72076 Tuebingen, Germany E-mail: [email protected] tors (PRs), PR-A and PR-B. Several in vitro studies indicate Received October 15, 2010; accepted December 13, 2010; that progestogens can exert an antiproliferative effect by acti- previously published online March 8, 2011 vation of these receptors in human breast cancer cells w9–11x. Brought to you by | Charles Stuart University (Charles Stuart University) 2010/039 Authenticated | 172.16.1.226 Download Date | 2/15/12 5:39 AM Article in press - uncorrected proof 186 Neubauer et al.: Progestogens and possible mechanism of breast cancer risk These data are in contrast to the above mentioned clinical selection of stable integration events. Transfection rates were meas- data. Other data suggested a proliferative effect of synthetic ured by cotransfection of a GFP-expressing plasmid and immune progestogens w12, 13x. Thus, the mechanisms by which pro- fluorescence analysis. After 2 weeks single colonies had formed and gestogens act on human breast cells remain unclear. limiting dilutions were performed three times to select for colonies Recent experimental data revealed that in addition to the grown from a single cell. Stable transfection was verified by PCR using chromosomal intracellular-located receptors, PGRMC1 is associated with a w x DNA and primers spanning intron 1 to distinguish integrated membrane-associated progesterone receptor activity 3 . PGRMC1 cDNA from the chromosomal sequence. The sequences PGRMC1 was originally cloned from the endoplasmatic of the primers were 59-CTGCTGCATGAGATTTTCACG-39 hybrid- reticulum from porcine hepatocytes w14x. It contains several izing to nucleotides 71–91 of PGRMC1 open reading frame and 59- predicted motifs for protein interactions and overlapping GCATAGTCCGGGACGTCATA-39 hybridizing to the sequence sites for phosphorylation, for which phosphorylation status coding for the HA tag. PCR products were sequenced. might correlate with its localization in the cell w3, 15, 16x. PGRMC1 has been detected in several cancers and cancer Dissolution of progestins cell lines, e.g., breast cancer w2, 17x. It is overexpressed in lung cancer and colon cancer w3x. Progesterone (P4), MPA, norethisterone (NET) and progesterone-3- There is a long-standing link between PGRMC1 and pro- (O-carboxymethyl) oxime: BSA-fluorescein-isothiocyanate conju- gate (P4-BSA-FITC) were purchased from Sigma (Munich, gesterone signaling. However, because bacterially expressed Germany) and drospirenone (DRSP) from Schering (Berlin, Ger- PGRMC1 does not bind to progesterone w18x, and because –4 many). P4-BSA-FITC was dissolved in H2O and stored as 10 M the majority of PGRMC1 is not localized to the plasma at 48C for less than 1 week, whereas the other compounds were membrane w1, 19, 20x it is now tentatively assumed that dissolved in ethanol, stored as 10–2 Mat–208C and further diluted PGRMC1 does not bind P4 by itself w3x, but requires an during experiments to a final ethanol concentration of less than unknown protein that is associated only in partially purified 0.01%. PGRMC1 preparations w21x. PGRMC1-associated progester- one binding is functionally important in cancer cells because Cell proliferation progesterone inhibits apoptosis in granulosa cells, and this antiapoptotic activity requires PGRMC1 w21, 22x. However, All proliferation assays were conducted using stripped medium, i.e., it is unclear how PGRMC1 transduces antiapoptotic signal- phenol red-free medium with charcoal/dextran-treated fetal bovine serum (Thermo, Karlsruhe, Germany). Approximately 10,000 cells ing by progesterone. Expression of PGRMC1 has been iden- were seeded in normal medium per well in 96-well plates. On the tified in several subcellular compartments including cell next day the medium was changed to stripped medium and the cells membrane, cytoplasm, endoplasmatic reticulum and nucleus were incubated at 378C for 2 days. Afterwards, stripped medium (reviewed in w3x). Swiatek-De Lange et al. reported that containing progestogens at concentrations ranging from 10–9 Mto PGRMC1 localizes to the plasma membrane and microsomal 10–5 M was added. Cell proliferation was measured by MTT assay fraction of retinal cells w23x. Based on these data in this after 4 days of incubation as described earlier w17x. In brief, yellow study, we investigated receptor membrane-initiated actions of MTT w3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bro- progesterone and various synthetic progestins in MCF-7 mide, a tetrazolex was reduced to purple formazan in the mitochon- breast cancer
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