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In particular, integrative omics approaches offer a broader scope for exploring the molecular and biochemical complexity of breast cancer. Notably, metabolomics through high\u2010resolution magic angle spinning (HR\u2010MAS) NMR spectroscopy enables nondestructive metabolic profiling of intact tissue samples, preserving the native biochemical context and offering unique potential for refining breast cancer subtyping and gaining deeper insight into disease biology. However, the reproducibility and comparability of HR\u2010MAS\u2010based metabolomics across studies are still limited by methodological variations, underscoring the need for standardized and reliable protocols to manage the complexity of breast cancer tissue spectra. In this study, LCModel analysis in combination with the Electronic REference To access In\u00a0vivo Concentrations (ERETIC2) method as a quantitative reference was implemented for absolute metabolite quantification of breast cancer samples, providing a robust metabolic profiling approach. Generalized linear models were applied to evaluate the associations between quantified metabolites and tumor immunohistochemical classification, and transcriptomic correlation analysis was used to explore gene expression profiles underlying the observed metabolic alterations. A total of 27 metabolites were quantified from breast tumor samples spanning the Luminal A, Luminal B (human epidermal growth factor receptor 2\u2013negative, HER2\u2212), Luminal B (HER2+), and triple\u2010negative breast cancer (TNBC) subtypes. Strong positive associations were observed between phosphocholine (PCho), betaine (Bet), total choline (tCho), and total creatine (tCr) and immunohistochemical subtype, whereas alanine, glucose, and myo\u2010inositol showed negative associations. Notably, Luminal B (HER2\u2212) tumors exhibited the highest PCho levels, linked to upregulated expression of choline kinase alpha (CHKA) and other enzymes of the Kennedy pathway. In contrast, Luminal B (HER2+) tumors exhibited elevated levels of alanine (Ala), glucose (Glc), and myo\u2010inositol (Ins), indicating distinct metabolic reprogramming within the luminal subgroups. Additionally, this study highlights the potential role of betaine (Bet) in interconnecting metabolic and epigenetic pathways in breast cancer, as its concentrations were found to vary across subtypes and correlate with genes involved in fatty acid metabolism, DNA methylation, and estrogen signaling. Robust HR\u2010MAS NMR profiling captured subtype\u2010dependent metabolic signatures, and integrative analysis with transcriptomics identified gene expression differences associated with these signatures, thereby advancing the understanding of breast cancer heterogeneity.<\/jats:p>","DOI":"10.1002\/nbm.70386","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T05:12:01Z","timestamp":1788412321000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<sup>1<\/sup>\n                    H HR\u2010MAS NMR Metabolomics in Combination With Transcriptomic Correlation Provides New Insights Into Metabolic Heterogeneity Across Breast Cancer Immunohistochemical Subtypes"],"prefix":"10.1002","volume":"39","author":[{"given":"Irene","family":"Garcia\u2010Bocanegra","sequence":"first","affiliation":[{"name":"Servicio de Radiodiagn\u00f3stico Hospital Regional Universitario de M\u00e1laga  Malaga Spain"},{"name":"Instituto de Investigaci\u00f3n Biom\u00e9dica de M\u00e1laga y Plataforma en Nanomedicina \u2010 IBIMA Plataforma BIONAND  M\u00e1laga Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4804-7230","authenticated-orcid":false,"given":"Jesus David","family":"Urbano\u2010Gamez","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Biom\u00e9dica de M\u00e1laga y Plataforma en Nanomedicina \u2010 IBIMA Plataforma BIONAND  M\u00e1laga Spain"},{"name":"Biomedical Magnetic Resonance Laboratory\u2010BMRL Andalusian Public Foundation Progress and Health\u2010FPS  Seville Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5835-5264","authenticated-orcid":false,"given":"Antonio","family":"Perez\u2010Cardona","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Biom\u00e9dica de M\u00e1laga y Plataforma en Nanomedicina \u2010 IBIMA Plataforma BIONAND  M\u00e1laga Spain"},{"name":"Biomedical Magnetic Resonance Laboratory\u2010BMRL Andalusian Public Foundation Progress and Health\u2010FPS  Seville Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Barrios","sequence":"additional","affiliation":[{"name":"Statistics Department Computing Center (SGAI\u2010CSIC)  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Isabel","family":"Somoza\u2010Ram\u00edrez","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Biom\u00e9dica de M\u00e1laga y Plataforma en Nanomedicina \u2010 IBIMA Plataforma BIONAND  M\u00e1laga Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis","family":"Vicioso","sequence":"additional","affiliation":[{"name":"Servicio de Anatom\u00eda Patol\u00f3gica Hospital Universitario Virgen de la Victoria  Malaga Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Pardo\u2010Susacasa","sequence":"additional","affiliation":[{"name":"Servicio de Radiodiagn\u00f3stico Hospital Universitario Virgen de la Victoria  Malaga Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gema","family":"Diaz\u2010Cordoba","sequence":"additional","affiliation":[{"name":"Servicio de Radiodiagn\u00f3stico Hospital Universitario Virgen de la Victoria  Malaga Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Mercedes","family":"Acebal\u2010Blanco","sequence":"additional","affiliation":[{"name":"Servicio de Radiodiagn\u00f3stico Hospital Universitario Virgen de la Victoria  Malaga Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9535-9806","authenticated-orcid":false,"given":"Francisco","family":"Sendra\u2010Portero","sequence":"additional","affiliation":[{"name":"Departamento de Radiolog\u00eda y Medicina F\u00edsica, Facultad de Medicina Universidad de M\u00e1laga  M\u00e1laga Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2257-7682","authenticated-orcid":false,"given":"Maria Luisa","family":"Garcia\u2010Martin","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Biom\u00e9dica de M\u00e1laga y Plataforma en Nanomedicina \u2010 IBIMA Plataforma BIONAND  M\u00e1laga Spain"},{"name":"Biomedical Magnetic Resonance Laboratory\u2010BMRL Andalusian Public Foundation Progress and Health\u2010FPS  Seville Spain"},{"name":"Biomedical Research Networking Center in Bioengineering, Biomaterials &amp; 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