Vitamin D Regulates CXCL12/CXCR4 and Epithelial-to-Mesenchymal Transition in a Model of Breast Cancer Metastasis to Lung

• Published in: Endocrinology (Philadelphia) Vol. 162; no. 7; p. 1
• Main Authors: Li, Jiarong, Luco, Aimée-Lee, Camirand, Anne, St-Arnaud, René, Kremer, Richard
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 01.07.2021
• Subjects: Alfacalcidol; Animal models; Animals; Antigens; Breast cancer; Calcifediol; Calciferol; Cancer; Carcinogenesis; Carcinogens; Cell Line, Tumor; Chemokine CXCL12 - analysis; Chemokine CXCL12 - pharmacology; Chemokine CXCL12 - physiology; Chemokine receptors; Chemokines; CXCL12 protein; CXCR4 protein; Diet; DNA binding proteins; E-cadherin; Endocrinology; Epithelial-Mesenchymal Transition - physiology; Ethylenediaminetetraacetic acid; Female; Homeobox; Immunodeficiency; Invasiveness; Localization; Lung cancer; Lung Neoplasms - chemistry; Lung Neoplasms - secondary; Lungs; Mammary gland; Mammary Neoplasms, Experimental - pathology; Mammary Neoplasms, Experimental - physiopathology; Metastases; Metastasis; Mice; Neoplasm Invasiveness - physiopathology; Nutrient deficiency; Phenotypes; Receptors, CXCR4 - analysis; Receptors, CXCR4 - physiology; Signal Transduction; Stat3 protein; Stem cells; Stroma; Tumor antigens; Tumor cells; Tumors; Vimentin; Viruses; Vitamin D; Vitamin D - analogs & derivatives; Vitamin D - pharmacology; Vitamin D - physiology; Vitamin D Deficiency - pathology; Vitamin D Deficiency - physiopathology; Vitamin deficiency; Zinc finger proteins; Canada; Quebec; breast cancer; epithelial to mesenchymal transition; CXCL12; metastasis; vitamin D
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/endocr/bqab049

Abstract Vitamin D deficiency is associated with poor cancer outcome in humans, and administration of vitamin D or its analogs decreases tumor progression and metastasis in animal models. 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, 10−9M 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 ”seed” (primary tumor cell) and ”soil” (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.