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It is still unclear which DCIS will become invasive and which will remain indolent. Patients often receive surgery and radiotherapy, but this early intervention has not produced substantial decreases in late-stage disease. Sprouty proteins are important regulators of ERK\/MAPK signaling and have been studied in various cancers. We hypothesized that Sprouty4 is an endogenous inhibitor of ERK\/MAPK signaling and that its loss\/reduced expression is a mechanism by which DCIS lesions progress toward IDC, including triple-negative disease. Using immunohistochemistry, we found reduced Sprouty4 expression in IDC patient samples compared to DCIS, and that ERK\/MAPK phosphorylation had an inverse relationship to Sprouty4 expression. These observations were reproduced using a 3D culture model of disease progression. Knockdown of Sprouty4 in MCF10.DCIS cells increased ERK\/MAPK phosphorylation as well as their invasive capability, while overexpression of Sprouty4 in MCF10.CA1d IDC cells reduced ERK\/MAPK phosphorylation, invasion, and the aggressive phenotype exhibited by these cells. Immunofluorescence experiments revealed reorganization of the actin cytoskeleton and relocation of E-cadherin back to the cell surface, consistent with the restoration of adherens junctions. To determine whether these effects were due to changes in ERK\/MAPK signaling, MEK1\/2 was pharmacologically inhibited in IDC cells. Nanomolar concentrations of MEK162\/binimetinib restored an epithelial-like phenotype and reduced pericellular proteolysis, similar to Sprouty4 overexpression. From these data we conclude that Sprouty4 acts to control ERK\/MAPK signaling in DCIS, thus limiting the progression of these premalignant breast lesions.<\/jats:p>","DOI":"10.1371\/journal.pone.0252314","type":"journal-article","created":{"date-parts":[[2021,5,28]],"date-time":"2021-05-28T17:51:27Z","timestamp":1622224287000},"page":"e0252314","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":11,"title":["Sprouty4 negatively regulates ERK\/MAPK signaling and the transition from in situ to invasive breast ductal carcinoma"],"prefix":"10.1371","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6502-851X","authenticated-orcid":true,"given":"Ethan J.","family":"Brock","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryan M.","family":"Jackson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julie L.","family":"Boerner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Quanwen","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meredith A.","family":"Tennis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bonnie F.","family":"Sloane","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raymond R.","family":"Mattingly","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2021,5,28]]},"reference":[{"issue":"2","key":"pone.0252314.ref001","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1200\/JCO.2008.18.3103","article-title":"Ductal carcinoma in situ: state of the science and roadmap to advance the field","volume":"27","author":"HM Kuerer","year":"2009","journal-title":"J Clin Oncol"},{"issue":"3","key":"pone.0252314.ref002","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1093\/jnci\/djp482","article-title":"Ductal carcinoma in situ of the breast: a systematic review of incidence, treatment, and outcomes","volume":"102","author":"BA Virnig","year":"2010","journal-title":"J Natl Cancer Inst"},{"issue":"41","key":"pone.0252314.ref003","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1093\/jncimonographs\/lgq019","article-title":"Molecular markers for the diagnosis and management of ductal carcinoma in situ","volume":"2010","author":"K. 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