{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n HOXB13 is a homeodomain‐containing transcription factor that plays multifaceted roles in normal development and cancer. In the prostate, HOXB13 is essential for proper organogenesis and differentiation – for example, it is critical for ventral prostate morphogenesis and establishing epithelial identity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In adult prostate cells, HOXB13 regulates androgen receptor (AR) signaling by directly interacting with the AR’s DNA‐binding domain. This interaction can inhibit transcription from classical androgen response elements while also enabling transcription from promoters containing juxtaposed HOX response elements, thereby modulating androgen‐responsive proliferation, migration, and lipogenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " Importantly, germline mutations in HOXB13 – notably the recurrent G84E variant – are strongly associated with an increased risk of familial prostate cancer"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ", and HOXB13 has been implicated in reprogramming the AR cistrome in transformed prostate epithelium."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Further, HOXB13 is critical for the function of the constitutively active AR splice variant AR‐V7 in castration‐resistant prostate cancer, serving as an upstream regulator that promotes AR‐V7 binding to open chromatin and oncogenic target gene expression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In breast cancer, high HOXB13 expression—and particularly an elevated HOXB13 to IL17BR expression ratio—is associated with poor prognosis and resistance to tamoxifen therapy, possibly through direct downregulation of estrogen receptor α and activation of proliferative cytokine pathways."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "13"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In ovarian cancer, HOXB13 appears to exert pro‐proliferative and survival‐promoting effects, collaborating with other oncogenic pathways and conferring resistance to apoptosis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": " In contrast, studies in other tumor contexts have suggested a tumor‐suppressive role for HOXB13. For instance, forced HOXB13 expression in certain prostate and colorectal cancer models can inhibit β‐catenin/TCF4–mediated transcription and curb cell proliferation, while re‐expression in melanoma cells reduces colony formation and tumor growth."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "17"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, epigenetic mechanisms also regulate HOXB13 expression; for example, FTO‐mediated demethylation of HOXB13 mRNA in endometrial cancer leads to enhanced expression and subsequent activation of pro‐metastatic WNT pathway signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": " Collectively, these studies highlight that the functional impact of HOXB13 is highly context dependent—acting either as an oncogenic driver or as a growth suppressor—and underscore its importance both as a mediator of lineage‐specific transcriptional programs and as a potential biomarker and therapeutic target in diverse cancers.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Kyriakos D Economides, Mario R Capecchi "}, {"type": "b", "children": [{"type": "t", "text": "Hoxb13 is required for normal differentiation and secretory function of the ventral prostate."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Development (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/dev.00432"}], "href": "https://doi.org/10.1242/dev.00432"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12668621"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12668621"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "John D Norris, Ching-Yi Chang, Bryan M Wittmann, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The homeodomain protein HOXB13 regulates the cellular response to androgens."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.molcel.2009.10.020"}], "href": "https://doi.org/10.1016/j.molcel.2009.10.020"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19917249"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19917249"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Chaeyong Jung, Ran-Sook Kim, Hong-Ji Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "HOXB13 induces growth suppression of prostate cancer cells as a repressor of hormone-activated androgen receptor signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-04-1330"}], "href": "https://doi.org/10.1158/0008-5472.CAN-04-1330"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15604291"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15604291"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Charles M Ewing, Anna M Ray, Ethan M Lange, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Germline mutations in HOXB13 and prostate-cancer risk."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "N Engl J Med (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1056/NEJMoa1110000"}], "href": "https://doi.org/10.1056/NEJMoa1110000"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22236224"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22236224"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Jianfeng Xu, Ethan M Lange, Lingyi Lu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "HOXB13 is a susceptibility gene for prostate cancer: results from the International Consortium for Prostate Cancer Genetics (ICPCG)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Genet (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00439-012-1229-4"}], "href": "https://doi.org/10.1007/s00439-012-1229-4"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23064873"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23064873"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Mark M Pomerantz, Fugen Li, David Y Takeda, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The androgen receptor cistrome is extensively reprogrammed in human prostate tumorigenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Genet (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ng.3419"}], "href": "https://doi.org/10.1038/ng.3419"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26457646"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26457646"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Ken J Kron, Alexander Murison, Stanley Zhou, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TMPRSS2-ERG fusion co-opts master transcription factors and activates NOTCH signaling in primary prostate cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Genet (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ng.3930"}], "href": "https://doi.org/10.1038/ng.3930"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28783165"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28783165"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Adam Sharp, Ilsa Coleman, Wei Yuan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Androgen receptor splice variant-7 expression emerges with castration resistance in prostate cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Invest (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1172/JCI122819"}], "href": "https://doi.org/10.1172/JCI122819"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30334814"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30334814"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Adeline Berger, Nicholas J Brady, Rohan Bareja, et al. "}, {"type": "b", "children": [{"type": "t", "text": "N-Myc-mediated epigenetic reprogramming drives lineage plasticity in advanced prostate cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Invest (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1172/JCI127961"}], "href": "https://doi.org/10.1172/JCI127961"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31260412"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31260412"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Xiao-Jun Ma, Susan G Hilsenbeck, Wilson Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The HOXB13:IL17BR expression index is a prognostic factor in early-stage breast cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Oncol (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1200/JCO.2006.06.6944"}], "href": "https://doi.org/10.1200/JCO.2006.06.6944"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17008703"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17008703"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Matthew P Goetz, Vera J Suman, James N Ingle, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A two-gene expression ratio of homeobox 13 and interleukin-17B receptor for prediction of recurrence and survival in women receiving adjuvant tamoxifen."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Cancer Res (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/1078-0432.CCR-05-1263"}], "href": "https://doi.org/10.1158/1078-0432.CCR-05-1263"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16609019"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16609019"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Nilay Shah, Kideok Jin, Leigh-Ann Cruz, et al. "}, {"type": "b", "children": [{"type": "t", "text": "HOXB13 mediates tamoxifen resistance and invasiveness in human breast cancer by suppressing ERα and inducing IL-6 expression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-13-1178"}], "href": "https://doi.org/10.1158/0008-5472.CAN-13-1178"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23832664"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23832664"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Zuncai Wang, Sonika Dahiya, Heather Provencher, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The prognostic biomarkers HOXB13, IL17BR, and CHDH are regulated by estrogen in breast cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Cancer Res (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/1078-0432.CCR-07-0310"}], "href": "https://doi.org/10.1158/1078-0432.CCR-07-0310"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17975144"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17975144"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Jiangyong Miao, Zuncai Wang, Heather Provencher, et al. "}, {"type": "b", "children": [{"type": "t", "text": "HOXB13 promotes ovarian cancer progression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0707938104"}], "href": "https://doi.org/10.1073/pnas.0707938104"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17942676"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17942676"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Chaeyong Jung, Ran-Sook Kim, Sang-Jin Lee, et al. "}, {"type": "b", "children": [{"type": "t", "text": "HOXB13 homeodomain protein suppresses the growth of prostate cancer cells by the negative regulation of T-cell factor 4."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.can-03-2614"}], "href": "https://doi.org/10.1158/0008-5472.can-03-2614"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15126340"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15126340"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "C Jung, R-S Kim, H Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "HOXB13 is downregulated in colorectal cancer to confer TCF4-mediated transactivation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Br J Cancer (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.bjc.6602631"}], "href": "https://doi.org/10.1038/sj.bjc.6602631"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15928669"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15928669"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Viswanathan Muthusamy, Sekhar Duraisamy, C Matthew Bradbury, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Epigenetic silencing of novel tumor suppressors in malignant melanoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-06-1274"}], "href": "https://doi.org/10.1158/0008-5472.CAN-06-1274"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17145863"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17145863"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Lin Zhang, Yicong Wan, Zihan Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "FTO demethylates m6A modifications in HOXB13 mRNA and promotes endometrial cancer metastasis by activating the WNT signalling pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "RNA Biol (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1080/15476286.2020.1841458"}], "href": "https://doi.org/10.1080/15476286.2020.1841458"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33103587"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33103587"}]}]}]}