{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T03:12:35Z","timestamp":1792638755420,"version":"4.5.0"},"reference-count":47,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T00:00:00Z","timestamp":1778544000000},"content-version":"vor","delay-in-days":11,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:00:00Z","timestamp":1777593600000},"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":["J Biochem &amp;amp; Molecular Tox"],"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Triple\u2010negative breast cancer (TNBC) is characterized by hypoxia and impaired fidelity to DNA repair and the activation of survival pathways. However, the role of specific AKT isoforms, particularly AKT2, in regulating residual homologous recombination (HR) activity and PARP inhibitor sensitivity under hypoxic stress remains unclear. This study aimed to establish the effect of AKT2 on hypoxia\u2010induced defects in HR repair, DNA damage accretion, and therapeutic outcomes of PARP inhibition in TNBC. TNBC cells were cultured under chronic hypoxia (1% O\n                    <jats:sub>2<\/jats:sub>\n                    ) or normoxia. Western blotting was used to measure protein expression and activation of HR\u2010 and hypoxia\u2010related markers, including, pAKT (Ser473), RAD51, BRCA1, \u03b3H2AX, HIF\u20101\u03b1, and CHK1\/CHK2. Immunofluorescence was used to assess the presence of RAD51 foci following 4\u2009Gy of irradiation as a functional measure of HR activity. A cell viability assay was used to determine the sensitivity to olaparib. In vitro findings were confirmed in orthotopic xenograft models with stable AKT2 knockdown. Hypoxia in tumors was measured through pimonidazole staining and HIF\u20101\u03b1 expression. Hypoxia increases HIF\u20101\u03b1 expression and activates AKT signaling. In our model, chronic hypoxia suppressed RAD51, p\u2010BRCA1, and checkpoint signaling, whereas total BRCA1 did not change and RAD51 foci decreased, indicating impaired and context\u2010dependent disruption of HR. Only AKT2 silencing reduced RAD51 and p\u2010BRCA1 under hypoxia, indicating an isoform\u2010specific role for AKT2 in HR maintenance. In AKT2\u2010deficient hypoxic cells, there was accumulation of persistent \u03b3H2AX and a corresponding repair defect. Functionally, AKT2 loss significantly enhanced olaparib sensitivity, resulting in marked RAD51 loss, robust \u03b3H2AX accumulation, and decreased viability. Knockdown of AKT2 in vivo increased the efficacy of olaparib, decreasing tumor weight and hypoxia and increasing the extent of DNA damage and suppression of HR markers, demonstrating a synergistic disruption of hypoxia\u2010driven survival pathways. AKT2 plays a vital role in the regulation of the HR repair and hypoxia\u2010driven survival in TNBC. Although hypoxia impaired HR through suppression of RAD51, p\u2010BRCA1, and checkpoint signaling, AKT2 preserved residual HR activity required for tumor cell survival under hypoxic stress. Its loss disrupts HR components, enhances sustained DNA damage, inhibits tumor hypoxia and sensitizes hypoxic tumors dramatically to PARP inhibition. These findings support a mechanistic model in which AKT2 enables hypoxic TNBC cells to tolerate HR dysfunction and survive genotoxic stress, thereby contributing to therapeutic resistance. These results establish AKT2 as a therapeutic target to counteract resistance in hypoxia and increase the efficacy of PARP inhibitors in TNBC. Although AKT2\u2010selective inhibitors have been reported, they remain largely preclinical. Accordingly, our findings support AKT2 as a promising therapeutic target and warrant further validation using AKT2\u2010selective pharmacologic inhibition.\n                  <\/jats:p>","DOI":"10.1002\/jbt.70895","type":"journal-article","created":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T07:19:57Z","timestamp":1778570397000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["AKT2 Counteracts Hypoxia\u2010Induced Suppression of Homologous Recombination in Triple\u2010Negative Breast Cancer: A Targeted Approach to Sensitize Tumors to PARP Inhibition"],"prefix":"10.1002","volume":"40","author":[{"given":"Ying","family":"Liang","sequence":"first","affiliation":[{"name":"Thyroid and Breast Surgery The Second Affiliated Hospital of Kunming Medical University Kunming 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