{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T17:14:49Z","timestamp":1788974089673,"version":"build-2803163510"},"reference-count":71,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["1R16GM145545"],"award-info":[{"award-number":["1R16GM145545"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"award":["1R16GM145545"],"award-info":[{"award-number":["1R16GM145545"]}],"id":[{"id":"https:\/\/ror.org\/04q48ey07","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000027","name":"National Institute on Alcohol Abuse and Alcoholism","doi-asserted-by":"publisher","award":["U54 AA019765"],"award-info":[{"award-number":["U54 AA019765"]}],"id":[{"id":"10.13039\/100000027","id-type":"DOI","asserted-by":"publisher"}]},{"award":["U54 AA019765"],"award-info":[{"award-number":["U54 AA019765"]}],"id":[{"id":"https:\/\/ror.org\/02jzrsm59","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006545","name":"National Institute on Minority Health and Health Disparities","doi-asserted-by":"publisher","award":["U54 MD012392"],"award-info":[{"award-number":["U54 MD012392"]}],"id":[{"id":"10.13039\/100006545","id-type":"DOI","asserted-by":"publisher"}]},{"award":["U54 MD012392"],"award-info":[{"award-number":["U54 MD012392"]}],"id":[{"id":"https:\/\/ror.org\/0493hgw16","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Alcohol consumption is associated with increased breast cancer risk, partly due to the accumulation of toxic aldehydes like acetaldehyde, a carcinogenic byproduct of ethanol metabolism. Acetaldehyde Dehydrogenase 2 (ALDH2), a key mitochondrial enzyme, detoxifies acetaldehyde and other reactive aldehydes that drive oxidative stress, DNA damage, and hormonal dysregulation\u2014processes central to carcinogenesis. Although alcohol consumption has been implicated in breast cancer, the role of ALDH2 deficiency itself, in the absence of exogenous alcohol exposure, in mammary gland biology and cancer susceptibility remains unclear. Genetic variants that impair ALDH2 activity are highly prevalent in East Asian populations, where carriers of inactive ALDH2 alleles exhibit impaired aldehyde detoxification. While such individuals are more susceptible to alcohol-related cancers, the effects of ALDH2 deficiency on mammary gland development and homeostasis without alcohol exposure remain unexplored. To investigate the effects of ALDH2 deficiency on mammary proliferation and development, we utilized a C57BL\/6-based ALDH2 knockout (Aldh2\u2212\/\u2212) mouse model. Our findings revealed that Aldh2\u2212\/\u2212 mice displayed hyperproliferative mammary glands with increased epithelial cell density, ductal expansion, and increased numbers of Ki67+ cells. Flow cytometry analysis revealed expansion of luminal and basal epithelial subpopulations, accompanied by enhanced mammary epithelial stemness, as indicated by increased mammosphere formation and colony-forming efficiency. At the molecular level, ALDH2 deficiency activated oxidative stress pathways, reflected by elevated 8-OHdG, p38 MAPK, NF-\u03baB, and Nrf2 signaling, along with DNA damage responses involving p53 and H2A.X. We also identified a novel upregulation of RANK and RANKL in Aldh2\u2212\/\u2212 mammary glands, identifying the RANK\/RANKL upregulation associated with NF-\u03baB\/p38 MAPK activation and enhanced mammary stemness. Furthermore, hormonal dysregulation was observed, with a significant increase in ER\u03b1 and PR expression and phosphorylation. Dysregulated ER signaling correlated with enhanced erbB3 activation and downstream signaling, including the cyclin D1\u2013pRb-E2F1 axis. These findings suggest that ALDH2 deficiency, possibly through accumulated endogenous aldehydes, profoundly alters mammary morphogenesis, epithelial repopulation, and stemness. These effects are associated with activation of oxidative stress and DNA damage pathways, together with upregulation of RANKL, estrogen receptor and receptor tyrosine kinase signaling. This study is the first to identify ALDH2 deficiency as a novel factor associated with mammary epithelial alterations that may create a tissue state that could predispose to oncogenic transformation.<\/jats:p>","DOI":"10.3390\/cells15181632","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T16:43:16Z","timestamp":1788972196000},"page":"1632","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["ALDH2 Deficiency Promotes Mammary Epithelial Stemness and Proliferative Morphogenesis Through Oxidative Stress, RANKL Induction, and Estrogen Receptor Signaling"],"prefix":"10.3390","volume":"15","author":[{"given":"Zhikun","family":"Ma","sequence":"first","affiliation":[{"name":"Department of Biological and Biomedical Sciences, Julius L. Chambers Biomedical\/Biotechnology Research Institute, North Carolina Research Campus, North Carolina Central University, 500 Laureate Way, Kannapolis, NC 28081, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]},{"given":"Amanda B.","family":"Parris","sequence":"additional","affiliation":[{"name":"Department of Biological and Biomedical Sciences, Julius L. Chambers Biomedical\/Biotechnology Research Institute, North Carolina Research Campus, North Carolina Central University, 500 Laureate Way, Kannapolis, NC 28081, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Miles","family":"Lester","sequence":"additional","affiliation":[{"name":"Department of Biological and Biomedical Sciences, Julius L. Chambers Biomedical\/Biotechnology Research Institute, North Carolina Research Campus, North Carolina Central University, 500 Laureate Way, Kannapolis, NC 28081, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"given":"De\u2019ja","family":"Gissendanner","sequence":"additional","affiliation":[{"name":"Department of Biological and Biomedical Sciences, Julius L. Chambers Biomedical\/Biotechnology Research Institute, North Carolina Research Campus, North Carolina Central University, 500 Laureate Way, Kannapolis, NC 28081, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"given":"Vasilis","family":"Vasiliou","sequence":"additional","affiliation":[{"name":"Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT 06520, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"resources","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5239-2451","authenticated-orcid":false,"given":"Xiaohe","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Biological and Biomedical Sciences, Julius L. Chambers Biomedical\/Biotechnology Research Institute, North Carolina Research Campus, North Carolina Central University, 500 Laureate Way, Kannapolis, NC 28081, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e195","DOI":"10.1002\/mco2.195","article-title":"Aldehyde dehydrogenase in solid tumors and other diseases: Potential biomarkers and therapeutic targets","volume":"4","author":"Xia","year":"2023","journal-title":"MedComm"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Zhu, W., Feng, D., Shi, X., Wei, Q., and Yang, L. (2022). The Potential Role of Mitochondrial Acetaldehyde Dehydrogenase 2 in Urological Cancers From the Perspective of Ferroptosis and Cellular Senescence. Front. Cell Dev. Biol., 10.","DOI":"10.3389\/fcell.2022.850145"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e007487","DOI":"10.1136\/jitc-2023-007487","article-title":"Aldehyde dehydrogenase 2-mediated aldehyde metabolism promotes tumor immune evasion by regulating the NOD\/VISTA axis","volume":"11","author":"Chen","year":"2023","journal-title":"J. Immunother. Cancer"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1073\/pnas.81.1.258","article-title":"Molecular abnormality of an inactive aldehyde dehydrogenase variant commonly found in Orientals","volume":"81","author":"Yoshida","year":"1984","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1007\/s43657-021-00017-y","article-title":"Origin and Spread of the ALDH2 Glu504Lys Allele","volume":"1","author":"Zhang","year":"2021","journal-title":"Phenomics"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.annepidem.2023.05.013","article-title":"ALDH2 polymorphism, alcohol intake and the attributable burden of cancer in East Asia: Systematic review, meta-analysis, and modeling study","volume":"85","author":"Ng","year":"2023","journal-title":"Ann. Epidemiol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Chen, C.H., Wang, W.L., Hsu, M.H., and Mochly-Rosen, D. (2022). Alcohol Consumption, ALDH2 Polymorphism as Risk Factors for Upper Aerodigestive Tract Cancer Progression and Prognosis. Life, 12.","DOI":"10.3390\/life12030348"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e24789","DOI":"10.1002\/jcla.24789","article-title":"ALDH2 gene rs671 G > a polymorphism and the risk of colorectal cancer: A hospital-based study","volume":"36","author":"Zhang","year":"2022","journal-title":"J. Clin. Lab. Anal."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Choi, C.K., Yang, J., Kweon, S.S., Cho, S.H., Kim, H.Y., Myung, E., and Shin, M.H. (2021). Association between ALDH2 polymorphism and esophageal cancer risk in South Koreans: A case-control study. BMC Cancer, 21.","DOI":"10.1186\/s12885-021-07993-4"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1158\/1055-9965.EPI-08-0462","article-title":"Aldehyde dehydrogenase 2 and head and neck cancer: A meta-analysis implementing a Mendelian randomization approach","volume":"18","author":"Boccia","year":"2009","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"6564","DOI":"10.1038\/s41598-020-62361-9","article-title":"Role of aldehyde dehydrogenases, alcohol dehydrogenase 1B genotype, alcohol consumption, and their combination in breast cancer in East-Asian women","volume":"10","author":"Park","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1038\/bjc.2014.579","article-title":"Alcohol consumption and site-specific cancer risk: A comprehensive dose-response meta-analysis","volume":"112","author":"Bagnardi","year":"2015","journal-title":"Br. J. Cancer"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/s12929-017-0327-y","article-title":"ALDH2 polymorphism and alcohol-related cancers in Asians: A public health perspective","volume":"24","author":"Chang","year":"2017","journal-title":"J. Biomed. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"244","DOI":"10.2188\/jea.JE20081035","article-title":"Interaction of the effects of alcohol drinking and polymorphisms in alcohol-metabolizing enzymes on the risk of female breast cancer in Japan","volume":"19","author":"Kawase","year":"2009","journal-title":"J. Epidemiol."},{"key":"ref_15","unstructured":"Patel, V.B., Rajendram, R., and Preedy, V.R. (2018). Endogenous Mitochondrial Aldehyde Dehydrogenase-2 as an Antioxidant in Liver. The Liver: Oxidative Stress and Dietary Antioxidants, Academic Publisher."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1152\/physrev.00017.2013","article-title":"Targeting aldehyde dehydrogenase 2: New therapeutic opportunities","volume":"94","author":"Chen","year":"2014","journal-title":"Physiol. Rev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.freeradbiomed.2012.11.010","article-title":"Aldehyde dehydrogenases in cellular responses to oxidative\/electrophilic stress","volume":"56","author":"Singh","year":"2013","journal-title":"Free Radic. Biol. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1007\/978-981-13-6260-6_3","article-title":"ALDH2 and Cardiovascular Disease","volume":"1193","author":"Chen","year":"2019","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1007\/s10038-003-0046-y","article-title":"Genetic deficiency of a mitochondrial aldehyde dehydrogenase increases serum lipid peroxides in community-dwelling females","volume":"48","author":"Ohsawa","year":"2003","journal-title":"J. Hum. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"689","DOI":"10.3349\/ymj.2017.58.4.689","article-title":"Alcohol Consumption, Aldehyde Dehydrogenase 2 Gene Polymorphisms, and Cardiovascular Health in Korea","volume":"58","author":"Shin","year":"2017","journal-title":"Yonsei Med. J."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Gao, J., Hao, Y., Piao, X., and Gu, X. (2022). Aldehyde Dehydrogenase 2 as a Therapeutic Target in Oxidative Stress-Related Diseases: Post-Translational Modifications Deserve More Attention. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23052682"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1002\/hep.27036","article-title":"Aldehyde dehydrogenase 2 deficiency ameliorates alcoholic fatty liver but worsens liver inflammation and fibrosis in mice","volume":"60","author":"Kwon","year":"2014","journal-title":"Hepatology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1007\/s12199-016-0579-2","article-title":"Roles of defective ALDH2 polymorphism on liver protection and cancer development","volume":"21","author":"Matsumoto","year":"2016","journal-title":"Environ. Health Prev. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.alcohol.2016.02.004","article-title":"Heme oxygenase 1 protects ethanol-administered liver tissue in Aldh2 knockout mice","volume":"52","author":"Matsumoto","year":"2016","journal-title":"Alcohol"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1007\/s00204-011-0779-x","article-title":"Differential genotoxic effects of subchronic exposure to ethyl tertiary butyl ether in the livers of Aldh2 knockout and wild-type mice","volume":"86","author":"Weng","year":"2012","journal-title":"Arch. Toxicol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1007\/s12640-020-00180-6","article-title":"High Ethanol and Acetaldehyde Inhibit Glutamatergic Transmission in the Hippocampus of Aldh2-Knockout and C57BL\/6N Mice: An In Vivo and Ex Vivo Analysis","volume":"37","author":"Jamal","year":"2020","journal-title":"Neurotox. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1111\/acer.12215","article-title":"Dominance of the Inactive Asian Variant Over Activity and Protein Contents of Mitochondrial Aldehyde Dehydrogenase 2 in Human Liver","volume":"38","author":"Lai","year":"2014","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1111\/j.1530-0277.1998.tb03867.x","article-title":"Studies on the Enzymology of Aldehyde Dehydrogenase-2 in Genetically Modified HeLa Cells","volume":"22","author":"Crabb","year":"1998","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1111\/j.1530-0277.1991.tb00532.x","article-title":"Acetaldehyde Metabolism in Different Aldehyde Dehydrogenase-2 Genotypes","volume":"15","author":"Enomoto","year":"1991","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"S18","DOI":"10.1210\/en.2005-1131","article-title":"Endocrine-disrupting compounds and mammary gland development: Early exposure and later life consequences","volume":"147","author":"Fenton","year":"2006","journal-title":"Endocrinology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1038\/s42003-021-02201-2","article-title":"Mammary cell gene expression atlas links epithelial cell remodeling events to breast carcinogenesis","volume":"4","author":"Saeki","year":"2021","journal-title":"Commun. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.stem.2024.01.003","article-title":"Metabolic regulation of the hallmarks of stem cell biology","volume":"31","author":"Jackson","year":"2024","journal-title":"Cell Stem Cell"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.cmet.2018.06.006","article-title":"Targeting Breast Cancer Stem Cell State Equilibrium through Modulation of Redox Signaling","volume":"28","author":"Luo","year":"2018","journal-title":"Cell Metab."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.gendis.2018.05.001","article-title":"Breast cancer development and progression: Risk factors, cancer stem cells, signaling pathways, genomics, and molecular pathogenesis","volume":"5","author":"Feng","year":"2018","journal-title":"Genes Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e100852","DOI":"10.15252\/embj.2018100852","article-title":"Mammary stem cells and progenitors: Targeting the roots of breast cancer for prevention","volume":"38","author":"Tharmapalan","year":"2019","journal-title":"EMBO J."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Ma, Z., Parris, A.B., Howard, E.W., Davis, M., Cao, X., Woods, C., and Yang, X. (2020). In Utero Exposure to Bisphenol a Promotes Mammary Tumor Risk in MMTV-Erbb2 Transgenic Mice Through the Induction of ER-erbB2 Crosstalk. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21093095"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1264","DOI":"10.1093\/carcin\/bgy096","article-title":"Caloric restriction inhibits mammary tumorigenesis in MMTV-ErbB2 transgenic mice through the suppression of ER and ErbB2 pathways and inhibition of epithelial cell stemness in premalignant mammary tissues","volume":"39","author":"Ma","year":"2018","journal-title":"Carcinogenesis"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1007\/s10911-012-9257-1","article-title":"Isolation of mouse mammary epithelial subpopulations: A comparison of leading methods","volume":"17","author":"Smalley","year":"2012","journal-title":"J. Mammary Gland Biol. Neoplasia"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2218","DOI":"10.1016\/j.devcel.2025.06.032","article-title":"Defining breast epithelial cell types in the single-cell era","volume":"60","author":"Gray","year":"2025","journal-title":"Dev. Cell"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2614","DOI":"10.1038\/onc.2011.439","article-title":"CD49f and CD61 identify Her2\/neu-induced mammary tumor-initiating cells that are potentially derived from luminal progenitors and maintained by the integrin-TGF\u03b2 signaling","volume":"31","author":"Lo","year":"2012","journal-title":"Oncogene"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"7711","DOI":"10.1158\/0008-5472.CAN-08-1949","article-title":"The mammary progenitor marker CD61\/beta3 integrin identifies cancer stem cells in mouse models of mammary tumorigenesis","volume":"68","author":"Vaillant","year":"2008","journal-title":"Cancer Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1002\/path.2457","article-title":"Detection and analysis of mammary gland stem cells","volume":"217","author":"Stingl","year":"2009","journal-title":"J. Pathol."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Vomund, S., Sch\u00e4fer, A., Parnham, M.J., Br\u00fcne, B., and von Knethen, A. (2017). Nrf2, the Master Regulator of Anti-Oxidative Responses. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18122772"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"P\u00e9rez-Chac\u00f3n, G., Santamar\u00eda, P.G., Redondo-Pedraza, J., and Gonz\u00e1lez-Su\u00e1rez, E. (2025). RANK\/RANKL Signaling Pathway in Breast Development and Cancer. A Guide to Breast Cancer Research: From Cellular Heterogeneity and Molecular Mechanisms to Therapy, Springer.","DOI":"10.1007\/978-3-031-70875-6_16"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"a003178","DOI":"10.1101\/cshperspect.a003178","article-title":"Hormone action in the mammary gland","volume":"2","author":"Brisken","year":"2010","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2334","DOI":"10.1158\/2159-8290.CD-20-1114","article-title":"RB\/E2F1 as a Master Regulator of Cancer Cell Metabolism in Advanced Disease","volume":"11","author":"Mandigo","year":"2021","journal-title":"Cancer Discov."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Kumar, R., Mishra, A., Gautam, P., Feroz, Z., Vijayaraghavalu, S., Likos, E.M., Shukla, G.C., and Kumar, M. (2022). Metabolic Pathways, Enzymes, and Metabolites: Opportunities in Cancer Therapy. Cancers, 14.","DOI":"10.3390\/cancers14215268"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1152\/physrev.00040.2018","article-title":"Stem Cells and the Differentiation Hierarchy in Mammary Gland Development","volume":"100","author":"Fu","year":"2020","journal-title":"Physiol. Rev."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Biswas, S.K., Banerjee, S., Baker, G.W., Kuo, C.Y., and Chowdhury, I. (2022). The Mammary Gland: Basic Structure and Molecular Signaling during Development. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23073883"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"a003244","DOI":"10.1101\/cshperspect.a003244","article-title":"The role of the microenvironment in mammary gland development and cancer","volume":"2","author":"Polyak","year":"2010","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Baratta, M., Miretti, S., Macchi, E., Accornero, P., and Martignani, E. (2018). Mammary Stem Cells in Domestic Animals: The Role of ROS. Antioxidants, 8.","DOI":"10.3390\/antiox8010006"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"7464","DOI":"10.1158\/0008-5472.CAN-04-1725","article-title":"Invasive potential induced under long-term oxidative stress in mammary epithelial cells","volume":"64","author":"Mori","year":"2004","journal-title":"Cancer Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"3177","DOI":"10.1038\/s41388-022-02329-3","article-title":"Role of p38 MAP kinase in cancer stem cells and metastasis","volume":"41","author":"Kudaravalli","year":"2022","journal-title":"Oncogene"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"114822","DOI":"10.1016\/j.biopha.2023.114822","article-title":"The role of NF-\u03baB in breast cancer initiation, growth, metastasis, and resistance to chemotherapy","volume":"163","author":"Pavitra","year":"2023","journal-title":"Biomed. Pharmacother."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1186\/s13041-015-0117-y","article-title":"Characterization of Aldh2\u2212\/\u2212 mice as an age-related model of cognitive impairment and Alzheimer\u2019s disease","volume":"8","author":"Elharram","year":"2015","journal-title":"Mol. Brain"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1038\/nature25154","article-title":"Alcohol and endogenous aldehydes damage chromosomes and mutate stem cells","volume":"553","author":"Garaycoechea","year":"2018","journal-title":"Nature"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1007\/s00018-018-2931-8","article-title":"Stem cells under the influence of alcohol: Effects of ethanol consumption on stem\/progenitor cells","volume":"76","author":"Baldari","year":"2019","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"695","DOI":"10.18632\/genesandcancer.156","article-title":"Alcohol, stem cells and cancer","volume":"8","author":"Gu","year":"2017","journal-title":"Genes. Cancer"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/s13046-018-1001-2","article-title":"RANKL\/RANK\/OPG system beyond bone remodeling: Involvement in breast cancer and clinical perspectives","volume":"38","author":"Infante","year":"2019","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Ming, J., Cronin, S.J.F., and Penninger, J.M. (2020). Targeting the RANKL\/RANK\/OPG Axis for Cancer Therapy. Front. Oncol., 10.","DOI":"10.3389\/fonc.2020.01283"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.tcb.2017.11.001","article-title":"RANKL and RANK: From Mammalian Physiology to Cancer Treatment","volume":"28","author":"Rao","year":"2018","journal-title":"Trends Cell Biol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1186\/1476-4598-12-86","article-title":"The complexity of NF-\u03baB signaling in inflammation and cancer","volume":"12","author":"Hoesel","year":"2013","journal-title":"Mol. Cancer"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1186\/bcr3166","article-title":"ER and PR signaling nodes during mammary gland development","volume":"14","author":"Tanos","year":"2012","journal-title":"Breast Cancer Res."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"5681","DOI":"10.1007\/s00018-021-03860-4","article-title":"Estrogen receptor-\u03b1 signaling in post-natal mammary development and breast cancers","volume":"78","author":"Chantalat","year":"2021","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Miziak, P., Baran, M., B\u0142aszczak, E., Przybyszewska-Podstawka, A., Ka\u0142afut, J., Smok-Kalwat, J., Dmoszy\u0144ska-Graniczka, M., Kie\u0142bus, M., and Stepulak, A. (2023). Estrogen Receptor Signaling in Breast Cancer. Cancers, 15.","DOI":"10.3390\/cancers15194689"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1007\/s10911-008-9077-5","article-title":"The role of ErbB3 and its binding partners in breast cancer progression and resistance to hormone and tyrosine kinase directed therapies","volume":"13","author":"Hamburger","year":"2008","journal-title":"J. Mammary Gland Biol. Neoplasia"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1083\/jcb.147.1.77","article-title":"ErbB4 signaling in the mammary gland is required for lobuloalveolar development and Stat5 activation during lactation","volume":"147","author":"Jones","year":"1999","journal-title":"J. Cell Biol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1177\/002215540004800107","article-title":"Changes in ErbB2 (her-2\/neu), ErbB3, and ErbB4 during growth, differentiation, and apoptosis of normal rat mammary epithelial cells","volume":"48","author":"Darcy","year":"2000","journal-title":"J. Histochem. Cytochem."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"4634","DOI":"10.1210\/en.2007-0148","article-title":"A functional serine 118 phosphorylation site in estrogen receptor-alpha is required for down-regulation of gene expression by 17beta-estradiol and 4-hydroxytamoxifen","volume":"148","author":"Cheng","year":"2007","journal-title":"Endocrinology"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2713","DOI":"10.1038\/s41598-018-21123-4","article-title":"Transcriptome analysis and prognosis of ALDH isoforms in human cancer","volume":"8","author":"Chang","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"e37820","DOI":"10.1097\/MD.0000000000037820","article-title":"ALDH2 as an immunological and prognostic biomarker: Insights from pan-cancer analysis","volume":"103","author":"Shen","year":"2024","journal-title":"Medicine"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/18\/1632\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T16:45:52Z","timestamp":1788972352000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/18\/1632"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,9]]},"references-count":71,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["cells15181632"],"URL":"https:\/\/doi.org\/10.3390\/cells15181632","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,9]]}}}