Targets of Vitamin D Receptor Signaling in the Mammary Gland

  title={Targets of Vitamin D Receptor Signaling in the Mammary Gland},
  author={JoEllen Welsh},
  journal={Journal of Bone and Mineral Research},
  • J. Welsh
  • Published 1 December 2007
  • Biology, Medicine
  • Journal of Bone and Mineral Research
Since the discovery of the vitamin D receptor (VDR) in mammary cells, the role of the vitamin D signaling pathway in normal glandular function and in breast cancer has been extensively explored. In vitro studies have shown that the VDR ligand, 1,25‐dihydroxyvitamin D (1,25D), modulates key proteins involved in signaling proliferation, differentiation, and survival of normal mammary epithelial cells. Similar anti‐proliferative and pro‐differentiating effects of 1,25D have been observed in VDR… 

Molecular Actions of the Vitamin D Receptor in Mammary and Skin Carcinogenesis

The data suggest that vitamin D regulation of cytokines is altered during the process of carcinogenesis and that the specific targets of VDR that regulate immune responses differ in human and mouse cells.

Vitamin D, Its Receptor Gene Polymorphism and Breast Cancer

The role of vitamin D and its receptor gene polymorphism in development of breast cancer development but controversial findings have been observed is still a matter of discussion.

Vitamin D and breast cancer: Inhibition of estrogen synthesis and signaling

Vitamin D and breast cancer.

The current evidence of the relationship between vitamin D and breast cancer is summarized, ongoing research in this area is highlighted, and optimal dosing of vitamin D for breast cancer prevention is discussed.

The Relationship Between Vitamin D and Breast Cancer Incidence and Natural History

The large Women’s Health Initiative failed to show any reduction in breast cancer incidence in postmenopausal women with a modest amount of vitamin D supplementation, and vitamin D is being investigated as a means to reduce aromatase inhibitor-induced joint symptoms.

Vitamin D and Reduction of Breast Cancer Risk

O Ongoing phase II trials in premenopausal women are designed to achieve levels of 25-OH D3 of ≥50 ng/mL and assess impact on risk biomarkers for breast cancer, and will inform design of future cancer incidence trials.

Influence of vitamin D signaling on hormone receptor status and HER2 expression in breast cancer

The possibility of actual and future targeted therapeutic approaches for vitamin D signaling in breast cancer are discussed, discussing especially the influence of vitaminD signaling on estrogen receptor and human epidermal growth factor receptor 2, two major biomarkers of breast cancer today.

Journal of Bone and Mineral Research

It is demonstrated that knockdown of the VDR strongly increases the metastatic potential of MDA‐MB‐231 human breast cancer cells to bone, resulting in significantly greater skeletal tumor burden.

Expression of 25-hydroxyvitamin D-1-alpha-hydroxylase, and vitamin D receptor mRNA in normal and malignant breast tissue.

The vitamin D axis expression in the breast suggests a role for its actions in normal tissue homeostasis and breast cancer pathogenesis, and 1alphaOHase expression was significantly down-regulated in adjacent non-cancerous tissue from women with breast cancer in comparison to individuals without cancer.



Identification of novel mediators of Vitamin D signaling and 1,25(OH)2D3 resistance in mammary cells

  • B. ByrneJ. Welsh
  • Biology
    The Journal of Steroid Biochemistry and Molecular Biology
  • 2007

Vitamin D and breast cancer: insights from animal models.

  • J. Welsh
  • Biology, Medicine
    The American journal of clinical nutrition
  • 2004
These studies support the concept that suboptimal generation of 1,25(OH)2D3 in the mammary gland might sufficiently deregulate VDR-mediated gene expression to sensitize mammary cells to transformation and define the most appropriate biomarkers of vitamin D status in relation to protection against breast cancer among human subjects.

Vitamin D-3 receptor as a target for breast cancer prevention.

Findings from cellular, molecular and population studies suggest that the VDR is a nutritionally modulated growth-regulatory gene that may represent a molecular target for chemoprevention of breast cancer.

Vitamin D(3) receptor ablation alters mammary gland morphogenesis.

The results indicate that mammary glands from virgin Vdr knockout mice are heavier and exhibit enhanced growth, as evidenced by higher numbers of terminal end buds, greater ductal outgrowth and enhanced secondary branch points, compared with glands from age- and weight-matched wild-type mice.

Mechanisms implicated in the growth regulatory effects of vitamin D compounds in breast cancer cells.

Although much remains to be learned about the associated underlying mechanisms, ongoing research suggests that vitamin D analogues are a new class of compounds with potential in breast cancer treatment and prevention.

Vitamin D receptor-dependent inhibition of mammary tumor growth by EB1089 and ultraviolet radiation in vivo.

Evidence is presented that both EB1089 and UV exposure inhibit tumor growth via induction of growth arrest and apoptosis and that therapeutic approaches designed to target the vitamin D pathway will be effective only if tumor cells express functional VDR.

Autocrine Metabolism of Vitamin D in Normal and Malignant Breast Tissue

The data indicate that the vitamin D–activating enzyme 1α-hydroxylase is up-regulated in breast tumors, and the enzymes involved in autocrine metabolism of vitamin D in breast tissue may provide important targets for both the prevention and treatment of breast cancer.

Vitamin D regulates the phenotype of human breast cancer cells.

Findings show that 1,25(OH)(2)D(3) profoundly affects the phenotype of breast cancer cells, and suggest that it reverts the myoepithelial features associated with more aggressive forms and poor prognosis in human breast cancer.

Altered Nuclear Receptor Corepressor Expression Attenuates Vitamin D Receptor Signaling in Breast Cancer Cells

Increased NCoR1 mRNA is a novel molecular lesion in breast cancer cells, which acts to suppress responsiveness of VDR target genes, resulting in 1α,25(OH)2D3 resistance and seems to be particularly associated with estrogen receptor negativity.

Role of Mitochondria and Caspases in Vitamin D-mediated Apoptosis of MCF-7 Breast Cancer Cells*

It is shown that 1α,25(OH)2D3 induces apoptosis in MCF-7 cells by disruption of mitochondrial function, which is associated with Bax translocation to mitochondria, cytochrome c release, and production of reactive oxygen species.