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Here, we reveal that transforming growth factor \u03b2 receptor 3 (TGFBR3) acts as an anoikis mediator through the coordination of activating transcription factor 4 (ATF4). In breast cancer tissues, TGFBR3 is progressively lost, but elevated TGFBR3 is associated with a histologic subtype characterized by cellular adhesion defects. Dissecting the impact of extracellular matrix (ECM) deprivation, we demonstrate that ECM loss promotes TGFBR3 expression, which in turn causes differentiation of cell aggregates, conferring a low-adhesion phenotype, and drives the intrinsic apoptotic pathway. We demonstrate that inhibition of TGFBR3 impairs epithelial anoikis by activating ATF4 signaling. These preclinical findings provide a rationale for therapeutic inhibition of ATF4 in the subgroup of breast cancer patients with low TGFBR3 expression.<\/jats:p>","DOI":"10.1242\/jcs.258396","type":"journal-article","created":{"date-parts":[[2022,8,1]],"date-time":"2022-08-01T09:24:00Z","timestamp":1659345840000},"source":"Crossref","is-referenced-by-count":5,"title":["TGFBR3 supports anoikis through suppressing ATF4 signaling"],"prefix":"10.1242","volume":"135","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1348-1416","authenticated-orcid":false,"given":"Yu-Jhen","family":"Hsu","sequence":"first","affiliation":[{"name":"Institute of Molecular Medicine, National Tsing Hua University 1 , Hsinchu 30013 , Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4264-1861","authenticated-orcid":false,"given":"Yih-Jia","family":"Yin","sequence":"additional","affiliation":[{"name":"Institute of Molecular Medicine, National Tsing Hua University 1 , Hsinchu 30013 , Taiwan"},{"name":"National Tsing Hua University 2 Department of Medical Science , , Hsinchu 30013 , Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2774-3379","authenticated-orcid":false,"given":"Kai-Feng","family":"Tsai","sequence":"additional","affiliation":[{"name":"Institute of Molecular Medicine, National Tsing Hua University 1 , Hsinchu 30013 , Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8990-1726","authenticated-orcid":false,"given":"Cian-Chun","family":"Jian","sequence":"additional","affiliation":[{"name":"Institute of Molecular Medicine, National Tsing Hua University 1 , Hsinchu 30013 , Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9416-2048","authenticated-orcid":false,"given":"Zi-Wen","family":"Liang","sequence":"additional","affiliation":[{"name":"Institute of Molecular Medicine, National Tsing Hua University 1 , Hsinchu 30013 , Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1323-4861","authenticated-orcid":false,"given":"Chien-Yu","family":"Hsu","sequence":"additional","affiliation":[{"name":"Institute of Molecular Medicine, National Tsing Hua University 1 , Hsinchu 30013 , Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4884-3835","authenticated-orcid":false,"given":"Chun-Chao","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Molecular Medicine, National Tsing Hua University 1 , Hsinchu 30013 , Taiwan"},{"name":"National Tsing Hua University 2 Department of Medical Science , , Hsinchu 30013 , Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2022,8,30]]},"reference":[{"key":"2022083010493937900_JCS258396C1","doi-asserted-by":"publisher","first-page":"1322","DOI":"10.1126\/science.281.5381.1322","article-title":"The Bcl-2 protein family: arbiters of cell survival","volume":"281","author":"Adams","year":"1998","journal-title":"Science"},{"key":"2022083010493937900_JCS258396C2","doi-asserted-by":"publisher","first-page":"418","DOI":"10.1016\/j.devcel.2017.10.027","article-title":"Tumor-suppressor inactivation of GDF11 occurs by precursor sequestration in triple-negative breast cancer","volume":"43","author":"Bajikar","year":"2017","journal-title":"Dev. 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