{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T18:55:59Z","timestamp":1785610559459,"version":"3.56.0"},"posted":{"date-parts":[[2026,7,31]]},"group-title":"Cancer Biology","reference-count":78,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T00:00:00Z","timestamp":1785456000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"NIH, BCRF, Susan G Komen, and other foundations"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,31]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Treatment resistance and metastases occur in 10\u201320% of patients with invasive lobular carcinoma (ILC), the most common special histological subtype of breast cancer. ILC metastasizes to the ovary more frequently than no special type (NST) tumors, also known as invasive ductal carcinoma (IDC). To characterize the genomic landscape of breast cancer ovarian metastases, we analyzed 15,613 local breast cancers, 22,010 non-ovarian metastases, and 246 ovarian metastases sequenced using FoundationOne\u00aeCDx or FoundationOne\u00ae assays. Ovarian metastases had enriched\n                  <jats:italic>CDH1<\/jats:italic>\n                  ,\n                  <jats:italic>PIK3CA<\/jats:italic>\n                  , and\n                  <jats:italic>TBX3<\/jats:italic>\n                  mutations and depleted\n                  <jats:italic>TP53<\/jats:italic>\n                  and\n                  <jats:italic>MYC<\/jats:italic>\n                  alterations relative to local breast cancers, with additional depletion of\n                  <jats:italic>ESR1<\/jats:italic>\n                  mutations compared to non-ovarian metastases.\n                  <jats:italic>CDH1<\/jats:italic>\n                  mutations were less frequent in ovarian metastases (47%) than local ILC (81.3%), with reduced 16q loss (64% vs 84%), indicating that ovarian metastases also arise from non-ILC tumors. We extended these findings to a UPMC cohort of 27 ovarian metastases (13 ILC, 8 IDC, 6 mixed ductal-lobular carcinoma) with patient-matched primary tumors in most cases. In both cohorts, patients with ovarian metastases were significantly younger than those with other metastatic sites. In the UPMC cohort, the most frequent mutations were in\n                  <jats:italic>PIK3CA<\/jats:italic>\n                  ,\n                  <jats:italic>CDH1<\/jats:italic>\n                  ,\n                  <jats:italic>KMT2C<\/jats:italic>\n                  ,\n                  <jats:italic>FOXA1<\/jats:italic>\n                  , and\n                  <jats:italic>RUNX1<\/jats:italic>\n                  . Transcriptomic analysis identified upregulated G protein-coupled receptor (GPCR) pathways, including metabotropic glutamate receptor signaling. Functional studies showed that calcium-sensing receptor (CaSR), a GPCR overexpressed in ovarian metastases, drives MEK\/ERK-dependent migration and F-actin reorganization in ILC cell lines, enhanced by estrogen and blocked by calcilytic, MEK, or anti- estrogen treatment. Our findings inform future therapeutic targeting of ovarian metastasis.\n                <\/jats:p>","DOI":"10.64898\/2026.07.30.741805","type":"posted-content","created":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T18:10:17Z","timestamp":1785607817000},"source":"Crossref","is-referenced-by-count":0,"title":["Breast cancer ovarian metastases show increased activity of GPCR pathways"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0452-9481","authenticated-orcid":false,"given":"Laura","family":"Savariau","sequence":"first","affiliation":[{"name":"Womens Cancer Research Center at UPMC Hillman Cancer Center and Magee Women\u2019s Research Institute, Pittsburgh, PA"},{"name":"Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye","family":"Qin","sequence":"additional","affiliation":[{"name":"Womens Cancer Research Center at UPMC Hillman Cancer Center and Magee Women\u2019s Research Institute, Pittsburgh, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4756-4535","authenticated-orcid":false,"given":"Osama","family":"Shah","sequence":"additional","affiliation":[{"name":"Womens Cancer Research Center at UPMC Hillman Cancer Center and Magee Women\u2019s Research Institute, Pittsburgh, PA"},{"name":"Integrative Systems Biology Program, University of Pittsburgh, Pittsburgh PA"},{"name":"University of Nebraska Medical Center, OM"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6689-7004","authenticated-orcid":false,"given":"Ahmed M","family":"Basudan","sequence":"additional","affiliation":[{"name":"Womens Cancer Research Center at UPMC Hillman Cancer Center and Magee Women\u2019s Research Institute, Pittsburgh, PA"},{"name":"Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh 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