Vitamin D counters bone invasion by mammary cancer through inhibition of inflammation and epithelial-to-mesenchymal transition
- 1Research Institute of the MUHC
Abstract
Vitamin D deficiency is associated with poor outcome in several cancers in humans, and administration of vitamin D or analogs has been shown to decrease tumor progression and metastasis in animal mammary cancer models. We previously demonstrated significant acceleration of carcinogenesis in vitamin D-deficient mouse mammary tumor virus-polyoma middle T (MMTV-PyMT) mammary cancer model as well as of its spontaneous metastasis to lungs. While vitamin D also plays a role in skeletal metastasis, detailed mechanisms of its promotion of bone invasion and metastatic events are not completely elucidated. In the present study we used tibially-injected MMTV-PyMT mammary tumor cells to analyse how dietary-induced vitamin D deficiency in non-immunodeficient FVB mice accelerates bone invasion. Mechanistically, we observed vitamin D deficiency to increase pro-inflammation cytokines and nestin expression in internal bone surface and marrow, and to increase epithelial-to-mesenchymal transition (EMT) through Zeb1 transcription factor. In vitro, treatment of MMTV-PyMT tumor cells with CXCL12 was observed to stimulate Zeb1 expression, and this effect was efficiently countered by 1,25(OH)2D treatment. Analysis of cytokines in MMTV-PyMT mammary tumor cells in vitro showed significant reduction in several pro-inflammatory cytokines with 1,25(OH)2D treatment (GM-CSF, ICAM-1, IL-1ra, IP-10, JE, MCP-5, MIP-1, MIP-1{beta}, MIP-2, RANTES and CXCL12), a crucial observation in view of the current evidence that inflammation is one of the hallmarks of cancer. Furthermore, vitamin D repleteness is associated with very high expression of Socs1 (suppressor of cytokine signalling 1), an inhibitor of JAK/STAT pathway which prevents excessive inflammatory responses and has a tumor-suppressive role. These findings provide a strong link between vitamin D deficiency and acceleration of inflammation-driven bone invasion, and nestin and EMT. The evidence suggests that vitamin D-repleteness in breast cancer patients could enhance the efficacy of co-administered therapies in preventing invasion of skeletal sites.
Related
- From inflammation to carcinogenesis: MiRNA regulates epithelial-mesenchymal transition to facilitate malignant progression of gastric precancerous lesions
- Isoliquiritigenin inhibits TGF-β1-induced epithelial–mesenchymal transition in pulmonary fibrosis by promoting Nix-mediated mitophagy
- UCHL1 Promotes Epithelial–Mesenchymal Transition Through E-Cadherin and N-Cadherin Switch in Endometrial Cancer
- Integrative Multi-Omics Reveals TSPAN13 as a Candidate Epithelial–Mesenchymal Transition-Associated Regulator in Prostate Cancer
- Keratin 17 Defines an Epithelial-Mesenchymal Transition-Associated Migratory Cell State in Pancreatic Ductal Adenocarcinoma
BibTeX
@misc{li2026vitamin,
title = {{Vitamin D counters bone invasion by mammary cancer through inhibition of inflammation and epithelial-to-mesenchymal transition}},
author = {J. Li and A.-L. Luco and A. Camirand and R. Kremer},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.02.748895},
url = {https://www.biorxiv.org/content/10.64898/2026.09.02.748895v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Vitamin D counters bone invasion by mammary cancer through inhibition of inflammation and epithelial-to-mesenchymal transition
AU - J. Li
AU - A.-L. Luco
AU - A. Camirand
AU - R. Kremer
PY - 2026
DA - 2026/09/02
PB - bioRxiv
DO - 10.64898/2026.09.02.748895
UR - https://www.biorxiv.org/content/10.64898/2026.09.02.748895v1
AB - Vitamin D deficiency is associated with poor outcome in several cancers in humans, and administration of vitamin D or analogs has been shown to decrease tumor progression and metastasis in animal mammary cancer models. We previously demonstrated significant acceleration of carcinogenesis in vitamin D-deficient mouse mammary tumor virus-polyoma middle T (MMTV-PyMT) mammary cancer model as well as of its spontaneous metastasis to lungs. While vitamin D also plays a role in skeletal metastasis, detailed mechanisms of its promotion of bone invasion and metastatic events are not completely elucidated. In the present study we used tibially-injected MMTV-PyMT mammary tumor cells to analyse how dietary-induced vitamin D deficiency in non-immunodeficient FVB mice accelerates bone invasion. Mechanistically, we observed vitamin D deficiency to increase pro-inflammation cytokines and nestin expression in internal bone surface and marrow, and to increase epithelial-to-mesenchymal transition (EMT) through Zeb1 transcription factor. In vitro, treatment of MMTV-PyMT tumor cells with CXCL12 was observed to stimulate Zeb1 expression, and this effect was efficiently countered by 1,25(OH)2D treatment. Analysis of cytokines in MMTV-PyMT mammary tumor cells in vitro showed significant reduction in several pro-inflammatory cytokines with 1,25(OH)2D treatment (GM-CSF, ICAM-1, IL-1ra, IP-10, JE, MCP-5, MIP-1, MIP-1{beta}, MIP-2, RANTES and CXCL12), a crucial observation in view of the current evidence that inflammation is one of the hallmarks of cancer. Furthermore, vitamin D repleteness is associated with very high expression of Socs1 (suppressor of cytokine signalling 1), an inhibitor of JAK/STAT pathway which prevents excessive inflammatory responses and has a tumor-suppressive role. These findings provide a strong link between vitamin D deficiency and acceleration of inflammation-driven bone invasion, and nestin and EMT. The evidence suggests that vitamin D-repleteness in breast cancer patients could enhance the efficacy of co-administered therapies in preventing invasion of skeletal sites.
ER -