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dc.contributor.authorAsperger, Hannah
dc.contributor.authorStamm, Nadia
dc.contributor.authorGierke, Berthold
dc.contributor.authorPawlak, Michael
dc.contributor.authorHofmann, Ute
dc.contributor.authorZanger, Ulrich M
dc.contributor.authorMarton, Annamaria
dc.contributor.authorKatona, Robert L
dc.contributor.authorBuhala, Andrea
dc.contributor.authorVizler, Csaba
dc.contributor.authorCieslik, Jan-Philipp
dc.contributor.authorRuckhäberle, Eugen
dc.contributor.authorNiederacher, Dieter
dc.contributor.authorFehm, Tanja
dc.contributor.authorNeubauer, Hans
dc.contributor.authorLudescher, Marina
dc.date.accessioned2021-02-15T05:22:42Z
dc.date.available2021-02-15T05:22:42Z
dc.date.issued2020
dc.identifier.issn1465-542X
dc.identifier.doi10.1186/s13058-020-01312-8
dc.identifier.urihttp://hdl.handle.net/10072/402159
dc.description.abstractBackground PGRMC1 (progesterone receptor membrane component 1) is a highly conserved heme binding protein, which is overexpressed especially in hormone receptor-positive breast cancer and plays an important role in breast carcinogenesis. Nevertheless, little is known about the mechanisms by which PGRMC1 drives tumor progression. The aim of our study was to investigate the involvement of PGRMC1 in cholesterol metabolism to detect new mechanisms by which PGRMC1 can increase lipid metabolism and alter cancer-related signaling pathways leading to breast cancer progression. Methods The effect of PGRMC1 overexpression and silencing on cellular proliferation was examined in vitro and in a xenograft mouse model. Next, we investigated the interaction of PGRMC1 with enzymes involved in the cholesterol synthesis pathway such as CYP51, FDFT1, and SCD1. Further, the impact of PGRMC1 expression on lipid levels and expression of enzymes involved in lipid homeostasis was examined. Additionally, we assessed the role of PGRMC1 in key cancer-related signaling pathways including EGFR/HER2 and ERα signaling. Results Overexpression of PGRMC1 resulted in significantly enhanced proliferation. PGRMC1 interacted with key enzymes of the cholesterol synthesis pathway, alters the expression of proteins, and results in increased lipid levels. PGRMC1 also influenced lipid raft formation leading to altered expression of growth receptors in membranes of breast cancer cells. Analysis of activation of proteins revealed facilitated ERα and EGFR activation and downstream signaling dependent on PGRMC1 overexpression in hormone receptor-positive breast cancer cells. Depletion of cholesterol and fatty acids induced by statins reversed this growth benefit. Conclusion PGRMC1 may mediate proliferation and progression of breast cancer cells potentially by altering lipid metabolism and by activating key oncogenic signaling pathways, such as ERα expression and activation, as well as EGFR signaling. Our present study underlines the potential of PGRMC1 as a target for anti-cancer therapy.
dc.languageen
dc.publisherSpringer Science and Business Media LLC
dc.relation.ispartofpagefrom75
dc.relation.ispartofissue1
dc.relation.ispartofjournalBreast Cancer Research
dc.relation.ispartofvolume22
dc.subject.fieldofresearchOncology and Carcinogenesis
dc.subject.fieldofresearchcode1112
dc.titleProgesterone receptor membrane component 1 regulates lipid homeostasis and drives oncogenic signaling resulting in breast cancer progression
dc.typeJournal article
dcterms.bibliographicCitationAsperger, H; Stamm, N; Gierke, B; Pawlak, M; Hofmann, U; Zanger, UM; Marton, A; Katona, RL; Buhala, A; Vizler, C; Cieslik, J-P; Ruckhäberle, E; Niederacher, D; Fehm, T; Neubauer, H; Ludescher, M, Progesterone receptor membrane component 1 regulates lipid homeostasis and drives oncogenic signaling resulting in breast cancer progression, Breast Cancer Research, 2020, 22 (1), pp. 75
dcterms.licensehttp://creativecommons.org/licenses/by/4.0/
dc.date.updated2021-02-15T05:20:37Z
dc.description.versionVersion of Record (VoR)
gro.rights.copyright© The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made.
gro.hasfulltextFull Text
gro.griffith.authorRichardson, Des R.


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