{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,26]],"date-time":"2026-04-26T04:35:35Z","timestamp":1777178135979,"version":"3.51.4"},"reference-count":65,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T00:00:00Z","timestamp":1776729600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Kyoto Preventive Medical Center Cancer Grant in Aid","award":["5-050"],"award-info":[{"award-number":["5-050"]}]},{"name":"JSPS KAKENHI Scientific Research","award":["JP22K10489"],"award-info":[{"award-number":["JP22K10489"]}]},{"name":"JSPS KAKENHI Scientific Research","award":["JP25K02869"],"award-info":[{"award-number":["JP25K02869"]}]},{"name":"JSPS KAKENHI Challenging Research","award":["JP25K22737"],"award-info":[{"award-number":["JP25K22737"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Endocrine therapy is the mainstay for estrogen receptor (ER) \u03b1-positive breast cancer (BC), yet many patients display acquired resistance. We then screened natural compounds using human ER\u03b1-positive BC cells and identified perillyl alcohol (POH), a monoterpene from perilla, that reduces ER\u03b1 protein levels. Chemoproteome analysis using POH-immobilized nanomagnetic beads revealed adenine nucleotide translocase 2 (ANT2), a mitochondrial inner membrane protein, as a direct target of POH. Molecular dynamics (MD) simulations predicted POH binding to the central pore of ANT2, which functions in ATP transport. ANT2 depletion reduced ER\u03b1 levels, and public datasets indicate that high ANT2 expression correlates with poor prognosis in ER\u03b1-positive BC. POH also inhibited the growth of Tamoxifen- and Fulvestrant-resistant BC cells. RNA sequencing showed that fatty acid elongation-related genes were upregulated in Fulvestrant-resistant cells but downregulated by ANT2 depletion. Both ANT2 depletion and POH treatment led to the accumulation of intracellular lipid droplets in Fulvestrant-resistant cells, consistent with impaired fatty acid elongation. Finally, in silico screening using MD simulations identified venetoclax and nystatin as potential ANT2 pore binders. Both compounds reduced ER\u03b1 levels in ER\u03b1-positive BC cells and increased lipid droplet formation in Fulvestrant-resistant cells. These findings highlight ANT2 as a druggable target against endocrine-resistant BC.<\/jats:p>","DOI":"10.3390\/ijms27083704","type":"journal-article","created":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T16:10:44Z","timestamp":1776787844000},"page":"3704","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Identification of ANT2 as a Druggable Target for Endocrine-Resistant ER\u03b1-Positive Breast Cancer"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-8675-1757","authenticated-orcid":false,"given":"Erika","family":"Iguchi","sequence":"first","affiliation":[{"name":"Department of Endocrine and Breast Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9499-1161","authenticated-orcid":false,"given":"Motoki","family":"Watanabe","sequence":"additional","affiliation":[{"name":"Department of Molecular-Targeting Prevention, Kyoto Prefectural University of Medicine, 465 Kajii-cho Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaito","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"Artificial Intelligence Research Center, National Institute of Advanced Industrial Science and Technology (AIST), 2-4-7 Aomi, Koto-ku, Tokyo 135-0064, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5015-0379","authenticated-orcid":false,"given":"Shogen","family":"Boku","sequence":"additional","affiliation":[{"name":"Department of Clinical Oncology, Kansai Medical University Hospital, 2-3-1, Shinmachi, Hirakata 573-1191, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wataru","family":"Nishio","sequence":"additional","affiliation":[{"name":"Department of Molecular-Targeting Prevention, Kyoto Prefectural University of Medicine, 465 Kajii-cho Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chikage","family":"Kato","sequence":"additional","affiliation":[{"name":"Department of Endocrine and Breast Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4083-4432","authenticated-orcid":false,"given":"Midori","family":"Morita","sequence":"additional","affiliation":[{"name":"Department of Endocrine and Breast Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Koichi","family":"Sakaguchi","sequence":"additional","affiliation":[{"name":"Department of Endocrine and Breast Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2054-7655","authenticated-orcid":false,"given":"Michihiro","family":"Mutoh","sequence":"additional","affiliation":[{"name":"Department of Molecular-Targeting Prevention, Kyoto Prefectural University of Medicine, 465 Kajii-cho Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9508-5366","authenticated-orcid":false,"given":"Tomoshi","family":"Kameda","sequence":"additional","affiliation":[{"name":"Artificial Intelligence Research Center, National Institute of Advanced Industrial Science and Technology (AIST), 2-4-7 Aomi, Koto-ku, Tokyo 135-0064, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasuto","family":"Naoi","sequence":"additional","affiliation":[{"name":"Department of Endocrine and Breast Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,21]]},"reference":[{"key":"ref_1","first-page":"229","article-title":"Global Cancer Statistics 2022: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. 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