estetrol; estrogen receptor; breast cancer; progesterone; drospirenone; menopause; contraception
Abstract :
[en] Hormonal treatments, especially those used to treat menopause symptoms are known to increase breast cancer risk. It is thus necessary to identify new formulations with a better benefit/risk pro-file. The aim of this translational study was to evaluate the breast cancer risk associated to a combination of a natural estrogen, named estetrol, with progestogens such as natural progesterone and drospirenone. Since the assessment of breast cancer risk in patients during drug development is not possible given the requirement of long-term studies in large populations, this study provides new evidences that a therapeutic dose of estetrol for menopause treatment or contraception, combined with progesterone or drospirenone, may provide a better benefit/risk profile towards breast cancer risk compared to hormonal treatments currently available for patients.
Research Center/Unit :
Giga-Cancer - ULiège
Disciplines :
Oncology
Author, co-author :
Gallez, Anne ; Université de Liège - ULiège > GIGA Cancer - Tumours and development biology
Blacher, Silvia ; Université de Liège - ULiège > GIGA Cancer - Tumours and development biology
Maquoi, Erik ; Université de Liège - ULiège > GIGA Cancer - Tumours and development biology
Konradowski, Erika ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Département des sciences biomédicales et précliniques
Joiret, Marc ; Université de Liège - ULiège > GIGA In silico medecine - Biomechanics Research Unit
Primac, Irina; Université de Liège - ULiège > GIGA Cancer - Tumours and development biology
Gérard, Céline; Mithra Pharmaceuticals
Taziaux, Mélanie; Mithra Pharmaceuticals
Houtman, René; Precision Medicine Lab (NL)
Geris, Liesbet ; Université de Liège - ULiège > Département d'aérospatiale et mécanique > Génie biomécanique
Lenfant, Françoise; INSERM U1048 (France)
Marangoni, Elisabetta; Institut Curie (France)
Sounni, Nor Eddine ; Université de Liège - ULiège > GIGA Cancer - Tumours and development biology
Foidart, Jean-Michel ; Université de Liège - ULiège > Département des sciences cliniques > Département des sciences cliniques
Noël, Agnès ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie cellulaire et moléculaire
Pequeux, Christel ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Département des sciences biomédicales et précliniques
Beral, V.; Peto, R.; Pirie, K. Type and timing of menopausal hormone therapy and breast cancer risk: Individual participant meta-analysis of the worldwide epidemiological evidence. Lancet 2019, 394, 1159–1168. [CrossRef]
Department of Economic and Social Affairs. Contraceptive Use by Method 2019: Data Booklet; United Nations: New York, NY, USA, 2019.
Mørch, L.S.; Skovlund, C.W.; Hannaford, P.C.; Iversen, L.; Fielding, S.; Lidegaard, Ø. Contemporary hormonal contraception and the risk of breast cancer. N. Engl. J. Med. 2017, 377, 2228–2239. [CrossRef]
Calle, E.E.; Heath, C.W.; Miracle-McMahill, H.L.; Coates, R.J.; Liff, J.M.; Franceschi, S.; Talamini, R.; Chantarakul, N.; Koetsawang, S.; RachawatRachawat, D.; et al. Breast cancer and hormonal contraceptives: Collaborative reanalysis of individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 epidemiological studies. Lancet 1996, 347, 1713–1727.
Iversen, L.; Sivasubramaniam, S.; Lee, A.J.; Fielding, S.; Hannaford, P.C. Lifetime cancer risk and combined oral contraceptives: The Royal College of General Practitioners’ Oral Contraception Study. Am. J. Obstet. Gynecol. 2017, 216, 580.e1–580.e9. [CrossRef] [PubMed]
Hagen, A.A.; Barr, M.; Diczfalusy, E. Metabolism of 17-Beta-estradiol-4-14-C in early infancy. Acta Endocrinol. 1965, 49, 207–220. [CrossRef]
Visser, M.; Foidart, J.M.; Coelingh Bennink, H.J.T. In vitro effects of estetrol on receptor binding, drug targets and human liver cell metabolism. Climacteric 2008, 11, 64–68. [CrossRef] [PubMed]
Gaspard, U.; Taziaux, M.; Mawet, M.; Jost, M.; Gordenne, V.; Coelingh Bennink, H.J.T.; Lobo, R.A.; Utian, W.H.; Foidart, J.-M. A multicenter, randomized study to select the minimum effective dose of estetrol (E4) in postmenopausal women (E4Relief). Menopause 2020, 27, 848–857. [CrossRef]
Abot, A.; Fontaine, C.; Buscato, M.; Solinhac, R.; Flouriot, G.; Fabre, A.; Drougard, A.; Rajan, S.; Laine, M.; Milon, A.; et al. The uterine and vascular actions of estetrol delineate a distinctive profile of estrogen receptor α modulation, uncoupling nuclear and membrane activation. EMBO Mol. Med. 2014, 6, 1328–1346. [CrossRef]
Coelingh Bennink, H.J.T.; Heegaard, A.M.; Visser, M.; Holinka, C.F.; Christiansen, C. Oral bioavailability and bone-sparing effects of estetrol in an osteoporosis model. Climacteric 2008, 11, 2–14. [CrossRef]
Benoit, T.; Valera, M.-C.; Fontaine, C.; Buscato, M.; Lenfant, F.; Raymond-Letron, I.; Tremollieres, F.; Soulie, M.; Foidart, J.-M.; Game, X.; et al. Estetrol, a Fetal Selective Estrogen Receptor Modulator, Acts on the Vagina of Mice through Nuclear Estrogen Receptor α Activation. Am. J. Pathol. 2017, 187, 2499–2507. [CrossRef]
Visser, M.; Holinka, C.F.; Coelingh Bennink, H.J.T. First human exposure to exogenous single-dose oral estetrol in early postmenopausal women. Climacteric 2008, 11 (Suppl. 1), 31–40. [CrossRef] [PubMed]
Kuhl, H. Pharmacology of estrogens and progestogens: Influence of different routes of administration. Climacteric 2005, 8, 3–63. [CrossRef] [PubMed]
Mawet, M.; Maillard, C.; Klipping, C.; Zimmerman, Y.; Foidart, J.M.; Bennink, H.J.T.C. Unique effects on hepatic function, lipid metabolism, bone and growth endocrine parameters of estetrol in combined oral contraceptives. Eur. J. Contracept. Reprod. Health Care 2015, 20, 463–475. [CrossRef] [PubMed]
Hammond, G.L.; Hogeveen, K.N.; Visser, M.; Coelingh Bennink, H.J.T. Estetrol does not bind sex hormone binding globulin or increase its production by human HepG2 cells. Climacteric 2008, 11, 41–46. [CrossRef]
Apter, D.; Zimmerman, Y.; Beekman, L.; Mawet, M.; Maillard, C.; Foidart, J.M.; Coelingh Bennink, H.J.T. Bleeding pattern and cycle control with estetrol-containing combined oral contraceptives: Results from a phase II, randomised, dose-finding study (FIESTA). Contraception 2016, 94, 366–373. [CrossRef]
Apter, D.; Zimmerman, Y.; Beekman, L.; Mawet, M.; Maillard, C.; Foidart, J.-M.; Coelingh Bennink, H.J.T. Estetrol combined with drospirenone: An oral contraceptive with high acceptability, user satisfaction, well-being and favourable body weight control. Eur. J. Contracept. Reprod. Health Care 2017, 22, 260–267. [CrossRef]
Gérard, C.; Blacher, S.; Communal, L.; Courtin, A.; Tskitishvili, E.; Mestdagt, M.; Munaut, C.; Noel, A.; Gompel, A.; Péqueux, C.; et al. Estetrol is a weak estrogen antagonizing estradiol-dependent mammary gland proliferation. J. Endocrinol. 2014, 224, 85–95. [CrossRef]
Visser, M.; Coelingh Bennink, H.J.T.; Kloosterboer, H.J. Estetrol prevents and suppresses mammary tumors induced by DMBA in a rat model. Horm. Mol. Biol. Clin. Investig. 2012, 9, 95–103. [CrossRef]
Yue, W.; Verhoeven, C.; Bernnink, H.C.; Wang, J.P.; Santen, R.J. Pro-Apoptotic Effects of Estetrol on Long-Term Estrogen-Deprived Breast Cancer Cells and at Low Doses on Hormone-Sensitive Cells. Breast Cancer Basic Clin. Res. 2019, 13, 1–8. [CrossRef]
Singer, C.F.; Bennink, H.J.T.C.; Natter, C.; Steurer, S.; Rudas, M.; Moinfar, F.; Appels, N.; Visser, M.; Kubista, E. Antiestrogenic effects of the fetal estrogen estetrol in women with estrogen-receptor positive early breast cancer. Carcinogenesis 2014, 35, 2447–2451. [CrossRef]
Gérard, C.; Mestdagt, M.; Tskitishvili, E.; Communal, L.; Gompel, A.; Silva, E.; Arnal, J.-F.; Lenfant, F.; Noel, A.; Foidart, J.-M.; et al. Combined estrogenic and anti-estrogenic properties of estetrol on breast cancer may provide a safe therapeutic window for the treatment of menopausal symptoms. Oncotarget 2015, 6, 17621–17636. [CrossRef] [PubMed]
Abderrahman, B.; Maximov, P.Y.; Curpan, R.F.; Hanspal, J.S.; Fan, P.; Xiong, R.; Tonetti, D.A.; Thatcher, G.R.; Jordan, V.C. Pharmacology and Molecular Mechanisms of Clinically Relevant Estrogen Estetrol and Estrogen Mimic BMI-135 for the Treatment of Endocrine-Resistant Breast Cancer. Mol. Pharmacol. 2020, 98, 364–381. [CrossRef]
Jozan, S.; Kreitmann, B.; Bayard, F. Different effects of oestradiol, oestriol, oestetrol and of oestrone on human breast cancer cells (MCF-7) in long term tissue culture. Acta Endocrinol. 1981, 98, 73–80. [CrossRef]
Lin, E.Y.; Jones, J.G.; Li, P.; Zhu, L.; Whitney, K.D.; Muller, W.J.; Pollard, J.W. Progression to malignancy in the polyoma middle T oncoprotein mouse breast cancer model provides a reliable model for human diseases. Am. J. Pathol. 2003, 163, 2113–2126. [CrossRef]
Guy, C.T.; Cardiff, R.D.; Muller, W.J. Induction of mammary tumors by expression of polyomavirus middle T oncogene: A transgenic mouse model for metastatic disease. Mol. Cell. Biol. 1992, 12, 954–961. [CrossRef]
Coussy, F.; de Koning, L.; Lavigne, M.; Bernard, V.; Ouine, B.; Boulai, A.; El Botty, R.; Dahmani, A.; Montaudon, E.; Assayag, F.; et al. A large collection of integrated genomically characterized patient-derived xenografts highlighting the heterogeneity of triple-negative breast cancer. Int. J. Cancer 2019, 145, 1902–1912. [CrossRef] [PubMed]
Byrne, A.T.; Alférez, D.G.; Amant, F.; Annibali, D.; Arribas, J.; Biankin, A.V.; Bruna, A.; Budinská, E.; Caldas, C.; Chang, D.K.; et al. Interrogating open issues in cancer precision medicine with patient-derived xenografts. Nat. Rev. Cancer 2017, 17, 254–268. [CrossRef]
Montaudon, E.; Nikitorowicz-Buniak, J.; Sourd, L.; Morisset, L.; El Botty, R.; Huguet, L.; Dahmani, A.; Painsec, P.; Nemati, F.; Vacher, S.; et al. PLK1 inhibition exhibits strong anti-tumoral activity in CCND1-driven breast cancer metastases with acquired palbociclib resistance. Nat. Commun. 2020, 11, 4053. [CrossRef] [PubMed]
Lobo, R.A.; Archer, D.F.; Kagan, R.; Kaunitz, A.M.; Constantine, G.D.; Pickar, J.H.; Graham, S.; Bernick, B.; Mirkin, S. A 17beta Estradiol-Progesterone Oral Capsule for Vasomotor Symptoms in Postmenopausal Women: A Randomized Controlled Trial. Obstet. Gynecol. Surv. 2018, 132, 161–170. [CrossRef] [PubMed]
Pickar, J.H.; Bon, C.; Amadio, J.M.; Mirkin, S.; Bernick, B. Pharmacokinetics of the first combination 17beta-estradiol/progesterone capsule in clinical development for menopausal hormone therapy. Menopause 2015, 22, 2113–2126.
Devissaguet, J.P.; Brion, N.; Lhote, O.; Deloffre, P. Pulsed estrogen therapy: Pharmacokinetics of intranasal 17-beta-estradiol (S21400) in postmenopausal women and comparison with oral and transdermal formulations. Eur. J. Drug Metab. Pharmacokinet. 1999, 24, 265–271. [CrossRef] [PubMed]
Gérard, C.; Gallez, A.; Dubois, C.; Drion, P.; Delahaut, P.; Quertemont, E.; Noël, A.; Pequeux, C. Accurate Control of 17β-Estradiol Long-Term Release Increases Reliability and Reproducibility of Preclinical Animal Studies. J. Mammary Gland Biol. Neoplasia 2017, 22, 1–11. [CrossRef]
Nys, G.; Gallez, A.; Kok, M.G.M.; Cobraiville, G.; Servais, A.-C.; Piel, G.; Pequeux, C.; Fillet, M. Whole blood microsampling for the quantitation of estetrol without derivatization by liquid chromatography-tandem mass spectrometry. J. Pharm. Biomed. Anal. 2017, 140, 258–265. [CrossRef] [PubMed]
Péqueux, C.; Raymond-Letron, I.; Blacher, S.; Boudou, F.; Adlanmerini, M.; Fouque, M.J.; Rochaix, P.; Noël, A.; Foidart, J.M.; Krust, A.; et al. Stromal estrogen receptor-α promotes tumor growth by normalizing an increased angiogenesis. Cancer Res. 2012, 72, 3010–3019. [CrossRef]
Chantalat, E.; Boudou, F.; Laurell, H.; Palierne, G.; Houtman, R.; Melchers, D.; Rochaix, P.; Filleron, T.; Stella, A.; Burlet-Schiltz, O.; et al. The AF-1-deficient estrogen receptor ERα46 isoform is frequently expressed in human breast tumors. Breast Cancer Res. 2016, 18, 123. [CrossRef]
Coelingh Bennink, H.J.T.; Verhoeven, C.; Zimmerman, Y.; Visser, M.; Foidart, J.-M.; Gemzell-Danielsson, K. Pharmacokinetics of the fetal estrogen estetrol in a multiple-rising-dose study in postmenopausal women. Climacteric 2017, 20, 285–289. [CrossRef]
Horwitz, K.B.; Mcguire, W.L. Estrogen Control of Progesterone Receptor in Human Breast Cancer. Correlation with Nuclear Processing of Estrogen Receptor. J. Biol. Chem. 1978, 253, 2223–2228. [CrossRef]
Purdie, C.A.; Quinlan, P.; Jordan, L.B.; Ashfield, A.; Ogston, S.; Dewar, J.A.; Thompson, A.M. Progesterone receptor expression is an independent prognostic variable in early breast cancer: A population-based study. Br. J. Cancer 2014, 110, 565–572. [CrossRef]
Siersbæk, R.; Kumar, S.; Carroll, J.S. Signaling pathways and steroid receptors modulating estrogen receptor α function in breast cancer. Genes Dev. 2018, 32, 1141–1154. [CrossRef]
Houtman, R.; de Leeuw, R.; Rondaij, M.; Melchers, D.; Verwoerd, D.; Ruijtenbeek, R.; Martens, J.W.M.; Neefjes, J.; Michalides, R. Serine-305 Phosphorylation Modulates Estrogen Receptor Alpha Binding to a Coregulator Peptide Array, with Potential Application in Predicting Responses to Tamoxifen. Mol. Cancer Ther. 2012, 11, 805–816. [CrossRef]
Foulds, C.E.; Feng, Q.; Ding, C.; Bailey, S.; Hunsaker, T.L.; Malovannaya, A.; Hamilton, R.A.; Gates, L.A.; Zhang, Z.; Li, C.; et al. Proteomic analysis of coregulators bound to ERα on DNA and Nucleosomes reveals coregulator dynamics. Mol. Cell 2013, 51, 185–199. [CrossRef] [PubMed]
Dobrolecki, L.E.; Airhart, S.D.; Alferez, D.G.; Aparicio, S.; Behbod, F.; Bentires-Alj, M.; Brisken, C.; Bult, C.J.; Cai, S.; Clarke, R.B.; et al. Patient-derived xenograft (PDX) models in basic and translational breast cancer research. Cancer Metastasis Rev. 2016, 35, 547–573. [CrossRef]
Giretti, M.S.; Montt Guevara, M.M.; Cecchi, E.; Mannella, P.; Palla, G.; Spina, S.; Bernacchi, G.; Di Bello, S.; Genazzani, A.R.; Genazzani, A.D.; et al. Effects of Estetrol on Migration and Invasion in T47-D Breast Cancer Cells through the Actin Cytoskeleton. Front. Endocrinol. 2014, 5, 80. [CrossRef] [PubMed]
Yang, J.; Han, F.; Liu, W.; Chen, H.; Hao, X.; Jiang, X.; Yin, L.; Huang, Y.; Cao, J.; Zhang, H.; et al. ALX4, an epigenetically down regulated tumor suppressor, inhibits breast cancer progression by interfering Wnt/β-catenin pathway. J. Exp. Clin. Cancer Res. 2017, 36, 170. [CrossRef]
