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Herein, we shown that genetic and pharmacological inhibition of Shp1 in breast cancer cells induces accelerated cell migration and promotes a more invasive phenotype. Furthermore, we found that interleukin-8 (IL8), a chemokine with multiple pro-tumorigenic roles within the tumor microenvironment, directly modulates Shp1 activity. In breast cancer, IL8 elicits its functions through the binding to the CXCR2 receptor with the subsequent modulation of several intracellular signaling pathways. We show that in breast MCF7 cells, IL8 induces the PKC-mediated phosphorylation of Shp1 at Ser591, diminishing its enzymatic activity and impairing the dephosphorylation of PP2A; this enhances CXCR2 phosphorylation and alters receptor trafficking by promoting ubiquitination and degradation of CXCR2. This feedback mechanism limits IL8 signaling revealing a previously unrecognized mechanism of receptor turnover and signal attenuation. In addition, we found that Shp1-mediated regulation of CXCR2 directly influences IL8-driven invasiveness in a subtype-specific manner, affecting luminal and triple-negative breast cancer (TNBC) cells but not HER2-positive ones. Transcriptomic and pathway analyses further support Shp1 involvement in cytokine and GPCR signaling, particularly in TNBC, where its downregulation correlates with reduced survival and higher IL8 levels. Taken together, our findings elucidate a novel mechanism of IL8 signaling and identify Shp1 as a promising therapeutic target, highlighting the potential of modulating the CXCR2\u2013Shp1 axis to limit invasiveness and metastasis in aggressive breast cancer subtypes, particularly TNBC.<\/jats:p>","DOI":"10.1038\/s41419-026-08516-4","type":"journal-article","created":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T16:46:28Z","timestamp":1772469988000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Shp1 phosphatase regulates CXCR2 protein stability and IL8-mediated invasiveness in breast cancer"],"prefix":"10.1038","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2983-1716","authenticated-orcid":false,"given":"Marcello","family":"Monti","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1476-1287","authenticated-orcid":false,"given":"Pier Giorgio","family":"Amendola","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angela","family":"Filograna","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sabrina","family":"Gargiulo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0617-0233","authenticated-orcid":false,"given":"Marcello","family":"Allegretti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3614-751X","authenticated-orcid":false,"given":"Daniela","family":"Corda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9705-2418","authenticated-orcid":false,"given":"Alessia","family":"Varone","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,3,2]]},"reference":[{"key":"8516_CR1","first-page":"12","volume":"74","author":"RL Siegel","year":"2024","unstructured":"Siegel RL, Giaquinto AN, Jemal A. 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