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Using the mouse mammary tumor virus-polyoma middle T antigen (MMTV-PyMT) model of mammary cancer, we previously demonstrated a significant acceleration of carcinogenesis in animals on a low vitamin D diet and a reduction in spontaneous lung metastases when mice received vitamin D through perfusion. We investigate here the action mechanism for vitamin D in lung metastasis in the same non-immunodeficient model and demonstrate that it involves the control of epithelial to mesenchymal transition as well as interactions between chemokine C-X-C motif chemokine 12 (CXCL12) and its receptor C-X-C chemokine receptor type 4 (CXCR4). In vitro, 10\u22129M vitamin D treatment modifies the phenotype of MMTV-PyMT primary mammary tumor cells and significantly decreases their invasiveness and mammosphere formation capacity by 40% and 50%, respectively. Vitamin D treatment also inhibits phospho-signal transducer and activator of transcription 3 (p-STAT3), zinc finger E-box-binding homeobox 1 (Zeb1), and vimentin by 52%, 75%, and 77%, respectively, and increases E-cadherin by 87%. In vivo, dietary vitamin D deficiency maintains high levels of Zeb1 and p-STAT3 in cells from primary mammary tumors and increases CXCL12 expression in lung stroma by 64%. In lung metastases, vitamin D deficiency increases CXCL12\/CXCR4 co-localization by a factor of 2.5. These findings indicate an involvement of vitamin D in mammary cancer \u201dseed\u201d (primary tumor cell) and \u201dsoil\u201d (metastatic site) and link vitamin D deficiency to epithelial-to-mesenchymal transition (EMT), CXCL12\/CXCR4 signaling, and accelerated metastasis, suggesting vitamin D repleteness in breast cancer patients could enhance the efficacy of co-administered therapies in preventing spread to distant organs.<\/jats:p>","DOI":"10.1210\/endocr\/bqab049","type":"journal-article","created":{"date-parts":[[2021,3,11]],"date-time":"2021-03-11T09:57:54Z","timestamp":1615456674000},"source":"Crossref","is-referenced-by-count":36,"title":["Vitamin D Regulates CXCL12\/CXCR4 and Epithelial-to-Mesenchymal Transition in a Model of Breast Cancer Metastasis to Lung"],"prefix":"10.1210","volume":"162","author":[{"given":"Jiarong","family":"Li","sequence":"first","affiliation":[{"name":"Department of Medicine, McGill University Health Centre, Glen Site, Montr\u00e9al, QC, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aim\u00e9e-Lee","family":"Luco","sequence":"additional","affiliation":[{"name":"Department of Medicine, McGill University Health Centre, Glen Site, Montr\u00e9al, QC, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1943-4293","authenticated-orcid":false,"given":"Anne","family":"Camirand","sequence":"additional","affiliation":[{"name":"Department of Medicine, McGill University Health Centre, Glen Site, Montr\u00e9al, QC, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ren\u00e9","family":"St-Arnaud","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Faculty of Dentistry, Shriners Hospital, Montr\u00e9al, QC, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7053-2139","authenticated-orcid":false,"given":"Richard","family":"Kremer","sequence":"additional","affiliation":[{"name":"Department of Medicine, McGill University Health Centre, Glen Site, Montr\u00e9al, QC, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2021,3,9]]},"reference":[{"key":"2021121717315263700_CIT0001","article-title":"The impact of vitamin D in cancer, cancer treatment - conventional and innovative approaches, Let\u00edcia Rangel, IntechOpen. 2013. https:\/\/www.intechopen.com\/books\/cancer-treatment-conventional-and-innovative-approaches\/the-impact-of-vitamin-d-in-cancer","author":"vinh quoc Luong"},{"issue":"6 Suppl","key":"2021121717315263700_CIT0002","doi-asserted-by":"crossref","first-page":"1721S","DOI":"10.1093\/ajcn\/80.6.1721S","article-title":"Vitamin D and breast cancer: insights from animal 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