Alterations in Vitamin D signalling and metabolic pathways in breast cancer progression: a study of VDR, CYP27B1 and CYP24A1 expression in benign and malignant breast lesions.
BACKGROUND
Breast cancer is a heterogeneous disease associated with different patient prognosis and responses to therapy. Vitamin D has been emerging as a potential treatment for cancer, as it has been demonstrated that it modulates proliferation, apoptosis, invasion and metastasis, among others. It acts mostly through the Vitamin D receptor (VDR) and the synthesis and degradation of this hormone are regulated by the enzymes CYP27B1 and CYP24A1, respectively. We aimed to study the expression of these three proteins by immunohistochemistry in a series of breast lesions.


METHODS
We have used a cohort comprising normal breast, benign mammary lesions, carcinomas in situ and invasive carcinomas and assessed the expression of the VDR, CYP27B1 and CYP24A1 by immunohistochemistry.


RESULTS
The results that we have obtained show that all proteins are expressed in the various breast tissues, although at different amounts. The VDR was frequently expressed in benign lesions (93.5%) and its levels of expression were diminished in invasive tumours (56.2%). Additionally, the VDR was strongly associated with the oestrogen receptor positivity in breast carcinomas. CYP27B1 expression is slightly lower in invasive carcinomas (44.6%) than in benign lesions (55.8%). In contrast, CYP24A1 expression was augmented in carcinomas (56.0% in in situ and 53.7% in invasive carcinomas) when compared with that in benign lesions (19.0%).


CONCLUSIONS
From this study, we conclude that there is a deregulation of the Vitamin D signalling and metabolic pathways in breast cancer, favouring tumour progression. Thus, during mammary malignant transformation, tumour cells lose their ability to synthesize the active form of Vitamin D and respond to VDR-mediated Vitamin D effects, while increasing their ability to degrade this hormone.
Lopes
Nair
N
Institute of Molecular Pathology and Immunology of the University of Porto, Porto 4200-465, Portugal.
Sousa
Bárbara
B
Martins
Diana
D
Gomes
Madalena
M
Vieira
Daniella
D
Veronese
Luiz A
LA
Milanezi
Fernanda
F
Paredes
Joana
J
Costa
José L
JL
Schmitt
Fernando
F
D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D001940:Breast / Q000378:metabolism* / Q000473:pathology; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism / Q000473:pathology; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000378:metabolism / Q000473:pathology; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007124:Immunoenzyme Techniques; D053858:Metabolic Networks and Pathways; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D018167:Receptors, Calcitriol / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013250:Steroid Hydroxylases / Q000378:metabolism*; D014807:Vitamin D / Q000378:metabolism*; D065668:Vitamin D3 24-Hydroxylase
D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D014807:Vitamin D; D013250:Steroid Hydroxylases; C585549:CYP24A1 protein, human; D065668:Vitamin D3 24-Hydroxylase; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase