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Epigenetic alterations of the <jats:italic>Homeobox A2<\/jats:italic> (<jats:italic>HOXA2<\/jats:italic>) gene have recently garnered significant attention in the clinical management of various malignancies. However, the precise role of <jats:italic>HOXA2<\/jats:italic> in breast tumorigenesis has remained elusive. To address this point, we conducted high-throughput RNA sequencing and DNA methylation array studies on laser-microdissected human BC samples, paired with normal tissue samples. Additionally, we performed comprehensive in silico analyses using large public datasets: TCGA and METABRIC. The diagnostic performance of <jats:italic>HOXA2<\/jats:italic> was calculated by means of receiver operator characteristic curves. Its prognostic significance was assessed through immunohistochemical studies and Kaplan-Meier Plotter database interrogation. Moreover, we explored the function of <jats:italic>HOXA2<\/jats:italic> and its role in breast carcinogenesis through in silico, in vitro, and in vivo investigations. Our work revealed significant hypermethylation and downregulation of <jats:italic>HOXA2<\/jats:italic> in human BC tissues. Low <jats:italic>HOXA2<\/jats:italic> expression correlated with increased BC aggressiveness and unfavorable patient survival outcomes. Suppression of <jats:italic>HOXA2<\/jats:italic> expression significantly heightened cell proliferation, migration, and invasion in BC cells, and promoted tumor growth in mice. Conversely, transgenic <jats:italic>HOXA2<\/jats:italic> overexpression suppressed these cellular processes and promoted apoptosis of cancer cells. Interestingly, a strategy of pharmacological demethylation successfully restored <jats:italic>HOXA2<\/jats:italic> expression in malignant cells, reducing their neoplastic characteristics. Bioinformatics analyses, corroborated by in vitro experimentations, unveiled a novel implication of HOXA2 in the lipid metabolism of BC. Specifically, depletion of <jats:italic>HOXA2<\/jats:italic> leaded to a concomitantly decreased expression of <jats:italic>PPAR\u03b3<\/jats:italic> and its target <jats:italic>CIDEC<\/jats:italic>, a master regulator of lipid droplet (LD) accumulation, thereby resulting in reduced LD abundance in BC cells. In summary, our study identifies <jats:italic>HOXA2<\/jats:italic> as a novel prognosis-relevant tumor suppressor in the mammary gland.<\/jats:p>","DOI":"10.1038\/s41418-024-01430-2","type":"journal-article","created":{"date-parts":[[2025,1,20]],"date-time":"2025-01-20T11:08:25Z","timestamp":1737371305000},"page":"730-744","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Epigenetic regulation of HOXA2 expression affects tumor progression and predicts breast cancer patient survival"],"prefix":"10.1038","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6109-2768","authenticated-orcid":false,"given":"Fatima Domenica Elisa","family":"De Palma","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8355-7562","authenticated-orcid":false,"given":"Jonathan 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GK has been holding research contracts with Daiichi Sankyo, Eleor, Kaleido, Lytix Pharma, PharmaMar, Osasuna Therapeutics, Samsara Therapeutics, Sanofi, Tollys, and Vascage. GK has been consulting for Reithera. GK is on the Board of Directors of the Bristol Myers Squibb Foundation France. GK is a scientific co-founder of everImmune, Osasuna Therapeutics, Samsara Therapeutics, and Therafast Bio. GK is in the scientific advisory boards of Hevolution, Institut Servier, and Longevity Vision Funds. GK is the inventor of patents covering therapeutic targeting of aging, cancer, cystic fibrosis, and metabolic disorders. GK\u2019s wife, Laurence Zitvogel, has held research contracts with Glaxo Smyth Kline, Incyte, Lytix, Kaleido, Innovate Pharma, Daiichi Sankyo, Pilege, Merus, Transgene, 9\u2009m, Tusk, and Roche, was on the on the Board of Directors of Transgene, is a co-founder of everImmune, and holds patents covering the treatment of cancer and the therapeutic manipulation of the microbiota. GK\u2019s brother, Romano Kroemer, was an employee of Sanofi and now consults for Boehringer-Ingelheim. The funders had no role in the design of the study; in the writing of the manuscript, or in the decision to publish the results. All the other authors declare no conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"Human tissue samples have been used in agreement with regulatory and bioethics rules of the Istituto Nazionale Tumori - Fondazione G. Pascale Ethics Committee (protocol number 3 of 03\/25\/2009, Naples, Italy) []. All patients provided their written informed consent for the research purpose of these clinical materials according to the tenets of the Helsinki Declaration. Animal experiments were performed in compliance with the EU Directive 63\/2010 and the local Ethical Committee (\u201cC. Darwin\u201d registered at the French Ministry of Research, protocol #51068).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}]}}