{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T07:04:30Z","timestamp":1773731070432,"version":"3.50.1"},"reference-count":68,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2025,1,7]],"date-time":"2025-01-07T00:00:00Z","timestamp":1736208000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"FCT\u2014Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","award":["UIDP\/04378\/2020"],"award-info":[{"award-number":["UIDP\/04378\/2020"]}]},{"name":"FCT\u2014Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","award":["UIDB\/04378\/2020"],"award-info":[{"award-number":["UIDB\/04378\/2020"]}]},{"name":"FCT\u2014Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","award":["LA\/P\/0140\/2020"],"award-info":[{"award-number":["LA\/P\/0140\/2020"]}]},{"name":"FCT\u2014Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","award":["10.54499\/UIDB\/00102\/2020"],"award-info":[{"award-number":["10.54499\/UIDB\/00102\/2020"]}]},{"name":"FCT\u2014Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","award":["10.54499\/UIDP\/00102\/2020"],"award-info":[{"award-number":["10.54499\/UIDP\/00102\/2020"]}]},{"name":"Research Unit on Applied Molecular Biosciences\u2014UCIBIO","award":["UIDP\/04378\/2020"],"award-info":[{"award-number":["UIDP\/04378\/2020"]}]},{"name":"Research Unit on Applied Molecular Biosciences\u2014UCIBIO","award":["UIDB\/04378\/2020"],"award-info":[{"award-number":["UIDB\/04378\/2020"]}]},{"name":"Research Unit on Applied Molecular Biosciences\u2014UCIBIO","award":["LA\/P\/0140\/2020"],"award-info":[{"award-number":["LA\/P\/0140\/2020"]}]},{"name":"Research Unit on Applied Molecular Biosciences\u2014UCIBIO","award":["10.54499\/UIDB\/00102\/2020"],"award-info":[{"award-number":["10.54499\/UIDB\/00102\/2020"]}]},{"name":"Research Unit on Applied Molecular Biosciences\u2014UCIBIO","award":["10.54499\/UIDP\/00102\/2020"],"award-info":[{"award-number":["10.54499\/UIDP\/00102\/2020"]}]},{"name":"Associate Laboratory Institute for Health and Bioeconomy\u2014i4HB","award":["UIDP\/04378\/2020"],"award-info":[{"award-number":["UIDP\/04378\/2020"]}]},{"name":"Associate Laboratory Institute for Health and Bioeconomy\u2014i4HB","award":["UIDB\/04378\/2020"],"award-info":[{"award-number":["UIDB\/04378\/2020"]}]},{"name":"Associate Laboratory Institute for Health and Bioeconomy\u2014i4HB","award":["LA\/P\/0140\/2020"],"award-info":[{"award-number":["LA\/P\/0140\/2020"]}]},{"name":"Associate Laboratory Institute for Health and Bioeconomy\u2014i4HB","award":["10.54499\/UIDB\/00102\/2020"],"award-info":[{"award-number":["10.54499\/UIDB\/00102\/2020"]}]},{"name":"Associate Laboratory Institute for Health and Bioeconomy\u2014i4HB","award":["10.54499\/UIDP\/00102\/2020"],"award-info":[{"award-number":["10.54499\/UIDP\/00102\/2020"]}]},{"name":"Research Unit CERES","award":["UIDP\/04378\/2020"],"award-info":[{"award-number":["UIDP\/04378\/2020"]}]},{"name":"Research Unit CERES","award":["UIDB\/04378\/2020"],"award-info":[{"award-number":["UIDB\/04378\/2020"]}]},{"name":"Research Unit CERES","award":["LA\/P\/0140\/2020"],"award-info":[{"award-number":["LA\/P\/0140\/2020"]}]},{"name":"Research Unit CERES","award":["10.54499\/UIDB\/00102\/2020"],"award-info":[{"award-number":["10.54499\/UIDB\/00102\/2020"]}]},{"name":"Research Unit CERES","award":["10.54499\/UIDP\/00102\/2020"],"award-info":[{"award-number":["10.54499\/UIDP\/00102\/2020"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: Endocrine therapies that comprise anti-estrogens and aromatase inhibitors (AIs) are the standard treatment for estrogen receptor-positive (ER+) (Luminal A) breast cancer\u2014the most prevalent subtype. However, the emergence of resistance restricts their success by causing tumor relapse and re-growth, which demands a switch towards other therapeutic approaches in order to minimize or overcome resistance. Indeed, this clinical limitation highlights the search for new molecules to improve cancer treatment. Recently, strategies that address multiple targets have been emerging, and multi-target drugs have the potential to become the future anti-cancer molecules. Our group has been searching for new multi-target compounds, and as part of this, our study aims to understand the anti-cancer and multi-target potential of three new steroidal aromatase inhibitors (AIs): 7\u03b1-methylandrost-4-en-17-one (6), 7\u03b1-methylandrost-4-ene-3,17-dione (10a) and androsta-4,9(11)-diene-3,17-dione (13). Methods: Their in vitro actions and molecular mechanisms were elucidated in a sensitive ER+ aromatase-overexpressing breast cancer cell line, MCF-7aro cells, as well as in an AI-resistant ER+ breast cancer cell line, LTEDaro cells. Results: All the new AIs (10 \u00b5M) prevented the proliferation of MCF-7aro cells by arresting cell cycle progression. Interestingly, all AIs (10 \u00b5M) act as androgen receptor (AR) agonists and modulate ER levels, synthesis and signaling to induce the apoptosis of ER+ breast cancer cells. Additionally, these new AIs (10 \u00b5M) also re-sensitize resistant cells by promoting apoptosis, offering a therapeutic benefit. Conclusions: Overall, new steroidal polypharmacological compounds have been discovered that, by acting as AIs, ER modulators and AR agonists, impair ER+ breast cancer cell growth. Overall, this study is a breakthrough on drug discovery as it presents new molecules with appealing anti-cancer properties and multi-target action for the treatment of ER+ breast cancer.<\/jats:p>","DOI":"10.3390\/cancers17020165","type":"journal-article","created":{"date-parts":[[2025,1,7]],"date-time":"2025-01-07T05:06:34Z","timestamp":1736226394000},"page":"165","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["New Promising Steroidal Aromatase Inhibitors with Multi-Target Action on Estrogen and Androgen Receptors for Breast Cancer Treatment"],"prefix":"10.3390","volume":"17","author":[{"given":"Cristina","family":"Amaral","sequence":"first","affiliation":[{"name":"UCIBIO\u2014Applied Molecular Biosciences Unit, Laboratory of Biochemistry, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira, n\u00b0 228, 4050-313 Porto, Portugal"},{"name":"Associate Laboratory i4HB, Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira, n\u00b0 228, 4050-313 Porto, Portugal"}]},{"given":"Cristina F.","family":"Almeida","sequence":"additional","affiliation":[{"name":"UCIBIO\u2014Applied Molecular Biosciences Unit, Laboratory of Biochemistry, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira, n\u00b0 228, 4050-313 Porto, Portugal"},{"name":"Associate Laboratory i4HB, Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira, n\u00b0 228, 4050-313 Porto, Portugal"}]},{"given":"Maria Jo\u00e3o","family":"Valente","sequence":"additional","affiliation":[{"name":"National Food Institute, Technical University of Denmark, 2800 Kongens Lyngby, Denmark"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9824-4753","authenticated-orcid":false,"given":"Carla L.","family":"Varela","sequence":"additional","affiliation":[{"name":"Univ Coimbra, CERES, Coimbra, Portugal; Univ Coimbra, Coimbra Institute for Clinical and Biomedical Research (iCBR), Clinic Academic Center of Coimbra (CACC), Coimbra, Portugal; Univ Coimbra, Center for Innovative Biomedicine and Biotechnology (CIBB), Azinhaga de Santa Comba, P\u00f3lo III, P\u00f3lo das Ci\u00eancias da Sa\u00fade, 3000-548 Coimbra, Portugal"}]},{"given":"Saul C.","family":"Costa","sequence":"additional","affiliation":[{"name":"Univ Coimbra, Faculty of Pharmacy, Laboratory of Pharmaceutical Chemistry, Azinhaga de Santa Comba, P\u00f3lo III, P\u00f3lo das Ci\u00eancias da Sa\u00fade, 3000-548 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4229-5882","authenticated-orcid":false,"given":"Fernanda M. F.","family":"Roleira","sequence":"additional","affiliation":[{"name":"Univ Coimbra, CERES, Faculty of Pharmacy, Laboratory of Pharmaceutical Chemistry, Azinhaga de Santa Comba, P\u00f3lo III, P\u00f3lo das Ci\u00eancias da Sa\u00fade, 3000-548 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0390-3403","authenticated-orcid":false,"given":"Elisi\u00e1rio","family":"Tavares-da-Silva","sequence":"additional","affiliation":[{"name":"Univ Coimbra, CERES, Faculty of Pharmacy, Laboratory of Pharmaceutical Chemistry, Azinhaga de Santa Comba, P\u00f3lo III, P\u00f3lo das Ci\u00eancias da Sa\u00fade, 3000-548 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6822-3572","authenticated-orcid":false,"given":"Anne Marie","family":"Vinggaard","sequence":"additional","affiliation":[{"name":"National Food Institute, Technical University of Denmark, 2800 Kongens Lyngby, Denmark"}]},{"given":"Nat\u00e9rcia","family":"Teixeira","sequence":"additional","affiliation":[{"name":"UCIBIO\u2014Applied Molecular Biosciences Unit, Laboratory of Biochemistry, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira, n\u00b0 228, 4050-313 Porto, Portugal"},{"name":"Associate Laboratory i4HB, Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira, n\u00b0 228, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5787-9018","authenticated-orcid":false,"given":"Georgina","family":"Correia-da-Silva","sequence":"additional","affiliation":[{"name":"UCIBIO\u2014Applied Molecular Biosciences Unit, Laboratory of Biochemistry, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira, n\u00b0 228, 4050-313 Porto, Portugal"},{"name":"Associate Laboratory i4HB, Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira, n\u00b0 228, 4050-313 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Almeida, C.F., Oliveira, A., Ramos, M.J., Fernandes, P.A., Teixeira, N., and Amaral, C. 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