{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T00:12:24Z","timestamp":1768522344803,"version":"3.49.0"},"posted":{"date-parts":[[2025,3,7]]},"group-title":"Cancer Biology","reference-count":78,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,3,7]],"date-time":"2025-03-07T00:00:00Z","timestamp":1741305600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,3,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  The most widely used cell line for studying ductal carcinoma in situ (DCIS) premalignancy is the transformed breast epithelial cell line,\n                  <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/MCF10DCIS.com\">MCF10DCIS.com<\/jats:ext-link>\n                  . During its original clonal isolation and selection,\n                  <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/MCF10DCIS.com\">MCF10DCIS.com<\/jats:ext-link>\n                  acquired a heterozygous M452I mutation in the proprotein convertase PCSK5, which has never been reported in any human cancer. The mutation is noteworthy because PCSK5 matures GDF11, a TGF\u03b2-superfamily ligand that suppresses progression of triple-negative breast cancer. We asked here whether PCSK5\n                  <jats:sup>M452I<\/jats:sup>\n                  and its activity toward GDF11 might contribute to the unique properties of\n                  <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/MCF10DCIS.com\">MCF10DCIS.com<\/jats:ext-link>\n                  . Using an optimized in-cell GDF11 maturation assay, we found that overexpressed PCSK5\n                  <jats:sup>M452I<\/jats:sup>\n                  was measurably active but at a fraction of the wildtype enzyme. In a\n                  <jats:italic>\n                    PCSK5\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                  <\/jats:italic>\n                  clone of\n                  <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/MCF10DCIS.com\">MCF10DCIS.com<\/jats:ext-link>\n                  reconstituted with different PCSK5 alleles, PCSK5\n                  <jats:sup>M452I<\/jats:sup>\n                  was mildly defective in anterograde transport. However, the multicellular organization of PCSK5\n                  <jats:sup>M452I<\/jats:sup>\n                  addback cells in 3D matrigel cultures was significantly less compact than wildtype and indistinguishable from a PCSK5\n                  <jats:sup>T288P<\/jats:sup>\n                  null allele. Growth of intraductal\n                  <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/MCF10DCIS.com\">MCF10DCIS.com<\/jats:ext-link>\n                  xenografts was similarly impaired along with the frequency of comedo necrosis and stromal activation. In no setting did PCSK5\n                  <jats:sup>M452I<\/jats:sup>\n                  exhibit gain-of-function activity, leading us to conclude that it is hypomorphic and thus compensated by the remaining wildtype allele in\n                  <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/MCF10DCIS.com\">MCF10DCIS.com<\/jats:ext-link>\n                  .\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Implications<\/jats:title>\n                  <jats:p>\n                    This work reassures that an exotic PCSK5 mutation is not responsible for the salient characteristics of the\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/MCF10DCIS.com\">MCF10DCIS.com<\/jats:ext-link>\n                    cell line.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.03.03.641323","type":"posted-content","created":{"date-parts":[[2025,3,7]],"date-time":"2025-03-07T17:55:20Z","timestamp":1741370120000},"source":"Crossref","is-referenced-by-count":0,"title":["PCSK5\n                  <sup>M452I<\/sup>\n                  is a recessive hypomorph exclusive to MCF10DCIS.com cells"],"prefix":"10.64898","author":[{"given":"Taylor","family":"Marohl","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kristen A.","family":"Atkins","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lixin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8028-6138","authenticated-orcid":false,"given":"Kevin 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