Mass spectrometry imaging shows specific lipids signals linked to Cyp27b1 ablation in the MMTV PyMT breast cancer model

Abstract

Bioactive vitamin D (1,25-dihydoxyvitamin D or 1,25(OH)2D) is synthesized from its inert circulating form 25-hydroxyvitamin D (25(OH)D) by the enzyme 1--hydroxylase in the kidneys and in other tissues including breast. Because breast cancer is associated with changes in intra-tumoral lipid composition and vitamin D is known to affect lipid metabolism, we investigated the potential role of tumor-produced 1,25(OH)2D on lipid profile expression during breast tumor progression. For that purpose, we used the MMTV-PyMT mouse model which mimics the four phases of tumor progression seen in human breast cancer (hyperplasia, adenoma/mammary intraepithelial neoplasia (MIN), early carcinoma and late carcinoma). In previous studies we showed that conditional ablation of the gene encoding 1--hydroxylase (Cyp27b1), specifically in the mammary epithelium of this MMTV-PyMT mouse model, resulted in enhanced spontaneous tumor initiation and progression. In the present study, we used mass spectrometry imaging to compare lipid composition in the mammary glands of Cyp27b1 ablated and non-ablated MMTV-PyMT mice. In non-ablated control animals, we observed changes to specific lipid signals linked to stages of tumor progression. In particular, several discriminatory lipid signals were significantly up regulated throughout tumor progression. In ablated mice, absence of Cyp27b1 in the mammary epithelium was accompanied by different lipid signals in hyperplastic lesions. Several lipid signals were exclusively detected in non-ablated tumors but absent in hyperplasia. Our findings suggest that the tumor-produced 1,25(OH)2D known to play a key role in mammary tumor progression is mechanistically related to early changes in lipid composition seen prior to the development of hyperplasia.