{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T13:06:04Z","timestamp":1789563964447,"version":"build-2803163510"},"reference-count":45,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T00:00:00Z","timestamp":1776988800000},"content-version":"vor","delay-in-days":23,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Reports"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Hereditary breast cancer accounts for approximately 10% of all breast cancer cases, with germline\n                      <jats:italic>BRCA2<\/jats:italic>\n                      pathogenic variants (PVs) being the most prevalent genetic alteration.\n                      <jats:italic>BRCA2<\/jats:italic>\n                      PVs predominantly lead to estrogen receptor (ER)\u2010positive\/HER2\u2010negative breast cancers, which exhibit more aggressive phenotypes compared to sporadic cases. However, the specific effect of\n                      <jats:italic>BRCA2<\/jats:italic>\n                      deficiency on ER signaling remains poorly understood.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>\n                      This study aimed to elucidate the relationship between\n                      <jats:italic>BRCA2<\/jats:italic>\n                      deficiency and ER signaling using integrated clinical and in vitro analyses.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and Results<\/jats:title>\n                    <jats:p>\n                      Immunohistochemical analyses were performed on ER\u2010positive\/HER2\u2010negative breast tumors from\n                      <jats:italic>BRCA2<\/jats:italic>\n                      PV carriers (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u20098) and\n                      <jats:italic>BRCA2<\/jats:italic>\n                      wild\u2010type patients (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200959). Furthermore, two\n                      <jats:italic>BRCA2<\/jats:italic>\n                      \u2010deficient ER\u2010positive\/HER2\u2010negative MCF7 cell lines were generated using CRISPR\u2010Cas9 with two distinct guide RNAs targeting\n                      <jats:italic>BRCA2<\/jats:italic>\n                      , followed by Western blotting and functional assays. Immunohistochemical analyses demonstrated significantly lower levels of phosphorylated (p)\u2010ER Ser167, p\u2010AKT Ser473, and RB1 in\n                      <jats:italic>BRCA2<\/jats:italic>\n                      PV carriers compared to patients with\n                      <jats:italic>BRCA2<\/jats:italic>\n                      wild\u2010type (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.002, 0.018, and 0.037, respectively). Western blotting confirmed reduced p\u2010ER Ser167, p\u2010AKT Ser473, and RB1 levels in\n                      <jats:italic>BRCA2<\/jats:italic>\n                      \u2010deficient cells relative to parental MCF7 cells. Decreased ER and AKT phosphorylation was not associated with consistent changes in the expression levels of downstream estrogen\u2010responsive genes or proteins. Functional assays revealed that\n                      <jats:italic>BRCA2<\/jats:italic>\n                      deficiency significantly increased sensitivity to the poly (ADP\u2010ribose) polymerase inhibitor olaparib, whereas tamoxifen sensitivity remained unchanged.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      This study presents the first detailed characterization of ER signaling alterations in ER\u2010positive\/HER2\u2010negative breast cancers with germline\n                      <jats:italic>BRCA2<\/jats:italic>\n                      PVs, offering insights for the development of targeted therapeutic strategies for this patient population.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cnr2.70558","type":"journal-article","created":{"date-parts":[[2026,4,25]],"date-time":"2026-04-25T03:39:48Z","timestamp":1777088388000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Altered Estrogen Receptor Signaling Pathway in\n                    <scp>BRCA2<\/scp>\n                    \u2010Deficient Estrogen Receptor\u2010Positive\/\n                    <scp>HER2<\/scp>\n                    \u2010Negative Breast Cancer"],"prefix":"10.1002","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-8399-8666","authenticated-orcid":false,"given":"Kaori","family":"Kawasaki","sequence":"first","affiliation":[{"name":"Department of Breast and Endocrine Surgery Osaka University Graduate School of Medicine  Suita Osaka 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