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Chromosome instability (CIN, an increased rate of chromosome gains and losses) is believed to play a fundamental role in the development and evolution of HGSOC. Importantly, overexpression of Cyclin E1 protein induces CIN, and genomic amplification of <jats:italic>CCNE1<\/jats:italic> contributes to HGSOC pathogenesis in ~20% of patients. Cyclin E1 levels are normally regulated in a cell cycle-dependent manner by the SCF (<jats:underline>S<\/jats:underline>KP1\u2013<jats:underline>C<\/jats:underline>UL1\u2013<jats:underline>F<\/jats:underline>BOX) complex, an E3 ubiquitin ligase that includes the proteins SKP1 and CUL1. Conceptually, diminished <jats:italic>SKP1<\/jats:italic> or <jats:italic>CUL1<\/jats:italic> expression is predicted to underlie increases in Cyclin E1 levels and induce CIN.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>This study employs fallopian tube secretory epithelial cell models to evaluate the impact diminished <jats:italic>SKP1<\/jats:italic> or <jats:italic>CUL1<\/jats:italic> expression has on Cyclin E1 and CIN in both short-term (siRNA) and long-term (CRISPR\/Cas9) studies.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Single-cell quantitative imaging microscopy approaches revealed changes in CIN-associated phenotypes and chromosome numbers and increased Cyclin E1 in response to diminished <jats:italic>SKP1<\/jats:italic> or <jats:italic>CUL1<\/jats:italic> expression.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>These data identify <jats:italic>SKP1<\/jats:italic> and <jats:italic>CUL1<\/jats:italic> as novel CIN genes in HGSOC precursor cells that may drive early aetiological events contributing to HGSOC development.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1038\/s41416-021-01317-w","type":"journal-article","created":{"date-parts":[[2021,3,17]],"date-time":"2021-03-17T08:03:14Z","timestamp":1615968194000},"page":"1699-1710","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Reduced SKP1 and CUL1 expression underlies increases in Cyclin E1 and chromosome instability in cellular precursors of high-grade serous ovarian cancer"],"prefix":"10.1038","volume":"124","author":[{"given":"Chloe Camille","family":"Lepage","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michaela Cora Lynn","family":"Palmer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ally Catherina","family":"Farrell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole Marie","family":"Neudorf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zelda","family":"Lichtensztejn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3291-8628","authenticated-orcid":false,"given":"Mark William","family":"Nachtigal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0081-8737","authenticated-orcid":false,"given":"Kirk James","family":"McManus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,3,17]]},"reference":[{"key":"1317_CR1","doi-asserted-by":"publisher","first-page":"9","DOI":"10.20892\/j.issn.2095-3941.2016.0084","volume":"14","author":"BM Reid","year":"2017","unstructured":"Reid, B. 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FT194 and FT246 cells were a generous gift from Dr. R. Drapkin (University of Pennsylvania).","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"No individual person\u2019s data were used in this paper, and thus no consent for publication was required for these studies.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to publish"}},{"value":"Patient-related data (Fig. ) are based on the data generated by the TCGA Research Network and are available at . All descriptive statistics and statistical analyses presented in Figs. \u2013 are provided within Supplementary Tables SII\u2013SXII.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Data availability"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"This study was funded by CIHR (C.C.L.) and NSERC (M.C.L.P.) Canada Graduate Scholarships (MSc) and a University of Manitoba GETS Award (N.M.N.) with operational support provided by the Cancer Research Society (M.W.N. and K.J.M.) and the CancerCare Manitoba Foundation (M.W.N. and K.J.M.). The funders had no role in the design of the study, in the collection, analyses or interpretation of the data, in the writing of the paper, or in the decision to publish the results.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding information"}}]}}