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This study investigates Semaphorin 3C (SEMA3C) as an ER-associated autocrine growth factor in ER+ breast cancer. Public clinical datasets show higher SEMA3C mRNA in ER+ tumors, with positive correlation to ESR1. ER+ cell lines express more SEMA3C than normal mammary cells; ER siRNA reduces SEMA3C, while beta-estradiol induces it. Recombinant SEMA3C activates MAPK and AKT, whereas SEMA3C silencing or the SEMA3C pathway inhibitor B1SP suppresses ER signaling, inhibits proliferation, and induces apoptosis, including in tamoxifen-resistant models.",{"@graph":69,"@context":123},[70,84,106],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/dependency-of-tamoxifen-sensitive-and-resistant-er-breast-cancer-cells-on-semaphorin-3c-sema3c-for-growth/384902/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/dependency-of-tamoxifen-sensitive-and-resistant-er-breast-cancer-cells-on-semaphorin-3c-sema3c-for-growth/384902.png","ImageObject",300,407,{"name":92,"@type":93},"Sophia Brooks","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-28","2026-09-24",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",13,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"What role does SEMA3C play in ER+ breast cancer cell growth?","Question",{"text":113,"@type":114},"SEMA3C supports the growth of ER+ breast cancer cells. SEMA3C knockdown inhibits proliferation and promotes apoptosis, indicating a growth dependency on SEMA3C.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"How is SEMA3C regulated in relation to the estrogen receptor pathway?",{"text":118,"@type":114},"SEMA3C is regulated by ER signaling: ER siRNA suppresses SEMA3C, while beta-estradiol induces SEMA3C expression. SEMA3C expression also correlates with ESR1 expression in clinical datasets.",{"name":120,"@type":111,"acceptedAnswer":121},"Does targeting SEMA3C affect tamoxifen-resistant ER+ cancer cells?",{"text":122,"@type":114},"Yes. Tamoxifen-resistant cell models retain high SEMA3C levels despite treatment and remain dependent on SEMA3C. Inhibiting the SEMA3C pathway with B1SP reduces SEMA3C-driven signaling and decreases growth and survival.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},384902,1790456200,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":56,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145},962084925636,"https://ap-avatar.wpscdn.com/davatar_994ba38a5ba835b3df7d355c54d3ed8d","cells  \nArticle  \nDependency of Tamoxifen Sensitive and Resistant ER+ Breast Cancer Cells on Semaphorin 3C (SEMA3C) for Growth  \nSatyam Bhasin 1,2, Christopher Dusek 1,2, James W. Peacock 1,2, Artem Cherkasov 1,2, Yuzhuo Wang 1,2, Martin Gleave 1,2 and Christopher J. Ong 1,2, *  \nCitation: Bhasin, S.; Dusek, C.; Peacock, J.W.; Cherkasov, A.; Wang, Y.; Gleave, M.; Ong, C.J. Dependency of Tamoxifen Sensitive and Resistant ER+ Breast Cancer Cells on Semaphorin 3C (SEMA3C) for Growth. Cells 2023, 12, 1715. [https://](https://)[ ](https://)[doi.org/10.3390/cells12131715](doi.org/10.3390/cells12131715)  \nAcademic Editors: Tuula Kallunki and Juan A. Rosado  \nReceived: 5 May 2023  \nRevised: 17 June 2023  \nAccepted: 21 June 2023  \nPublished: 25 June 2023  \nCopyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) .  \n1 Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada; [sbhasin@prostatecentre.com](sbhasin@prostatecentre.com) (S.B.); [cdusek@prostatecentre.com](cdusek@prostatecentre.com) (C.D.); [jpeacock@prostatecentre.com](jpeacock@prostatecentre.com) (J.W.P.); [acherkasov@prostatecentre.com](acherkasov@prostatecentre.com) (A.C.); [ywang@prostatecentre.com](ywang@prostatecentre.com) (Y.W.); [m.gleave@ubc.ca](m.gleave@ubc.ca) (M.G.)  \n2 Department of Urologic Sciences, The University of British Columbia, Vancouver, BC V5Z 1M9, Canada  \n* Correspondence: [chris.ong@ubc.ca](chris.ong@ubc.ca); Tel.: +1-6048754111 (ext. 63120)  \nAbstract: Estrogen receptor positive (ER+ ) breast cancer (BCa) accounts for the highest proportion of breast cancer-related deaths. While endocrine therapy is highly effective for this subpopulation, endocrine resistance remains a major challenge and the identification of novel targets is urgently needed. Previously, we have shown that Semaphorin 3C (SEMA3C) is an autocrine growth factor that drives the growth and treatment resistance of various cancers, but its role in breast cancer progression and endocrine resistance is poorly understood. Here, we report that SEMA3C plays a role in maintaining the growth of ER+ BCa cells and is a novel, tractable therapeutic target for the treatment of ER+ BCa patients. Analyses of publicly available clinical datasets indicate that ER+ BCa patients express significantly higher levels of SEMA3C mRNA than other subtypes. Furthermore, SEMA3CmRNA expression was positively correlated with ESR1 mRNA expression. ER+ BCa cell lines (MCF7 and T47D) expressed higher levels of SEMA3C mRNA and protein than a normal mammary epithelial MCF10A cell line. ER siRNA knockdown was suppressed, while dose-dependent beta-estradiol treatment induced SEMA3C expression in both MCF7 and T47D cells, suggesting that SEMA3Cis an ER-regulated gene. The stimulation of ER+ BCa cells with recombinant SEMA3C activated MAPK and AKT signaling in a dose-dependent manner. Conversely, SEMA3C silencing inhibited Estrogen Receptor (ER) expression, MAPK and AKT signaling pathways while simultaneously inducing apoptosis, as monitored by flow cytometry and Western blot analyses. SEMA3C silencing significantly inhibited the growth of ER+ BCa cells, implicating a growth dependency of ER+ BCa cells on SEMA3C. Moreover, the analysis of tamoxifen resistant (TamR) cell models (TamC3 and TamR3) showed that SEMA3C levels remain high despite treatment with tamoxifen. Tamoxifen-resistant cells remained dependent on SEMA3C for growth and survival. Treatment with B1SP Fc fusion protein, a SEMA3C pathway inhibitor, attenuated SEMA3C-induced signaling and growth across a panel of tamoxifen sensitive and resistant ER+ breast cancer cells. Furthermore, SEMA3C silencing and B1SP treatment were associated with decreased EGFR signaling in TamR ","cbCaioCtPU8nleYd","https://ap.wps.com/l/cbCaioCtPU8nleYd","pdf",4231561,"English","# Abstract\n## Introduction","[{\"question\":\"What role does SEMA3C play in ER+ breast cancer cell growth?\",\"answer\":\"SEMA3C supports the growth of ER+ breast cancer cells. SEMA3C knockdown inhibits proliferation and promotes apoptosis, indicating a growth dependency on SEMA3C.\"},{\"question\":\"How is SEMA3C regulated in relation to the estrogen receptor pathway?\",\"answer\":\"SEMA3C is regulated by ER signaling: ER siRNA suppresses SEMA3C, while beta-estradiol induces SEMA3C expression. SEMA3C expression also correlates with ESR1 expression in clinical datasets.\"},{\"question\":\"Does targeting SEMA3C affect tamoxifen-resistant ER+ cancer cells?\",\"answer\":\"Yes. Tamoxifen-resistant cell models retain high SEMA3C levels despite treatment and remain dependent on SEMA3C. Inhibiting the SEMA3C pathway with B1SP reduces SEMA3C-driven signaling and decreases growth and survival.\"}]","Dependency of Tamoxifen Sensitive and Resistant ER+ Breast Cancer Cells on Semaphorin 3C (SEMA3C) for Growth | PDF",1790265723,48]