CrbpI regulates mammary retinoic acid homeostasis and the mammary microenvironment.
Cellular retinol-binding protein, type I (CrbpI), encoded by retinol-binding protein, type 1 (Rbp1), is a chaperone of vitamin A (retinol) that is epigenetically silenced in ~25% of human breast cancers. CrbpI delivers vitamin A to enzymes for metabolism into an active metabolite, all-trans retinoic acid (atRA), where atRA is essential to cell proliferation, apoptosis, differentiation, and migration. Here, we show the effect of CrbpI loss on mammary atRA homeostasis using the Rbp1(-/-) mouse model. Rbp1(-/-) mouse mammary tissue has disrupted retinoid homeostasis that results in 40% depleted endogenous atRA. CrbpI loss and atRA depletion precede defects in atRA biosynthesis enzyme expression. Compensation by CrbpIII as a retinoid chaperone does not functionally replace CrbpI. Mammary subcellular fractions isolated from Rbp1(-/-) mice have altered retinol dehydrogenase/reductase (Rdh) enzyme activity that results in 24-42% less atRA production. Rbp1(-/-) mammary tissue has epithelial hyperplasia, stromal hypercellularity, increased collagen, and increased oxidative stress characteristic of atRA deficiency and early tissue dysfunction that precedes tumor formation. Consistent with the findings from the Rbp1(-/-) mouse, tumorigenic epithelial cells lacking CrbpI expression produce 51% less atRA. Together, these data show that CrbpI loss disrupts atRA homeostasis in mammary tissue, resulting in microenvironmental defects similar to those observed at the early stages of tumorigenesis.
Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA.
Keely
K
Pierzchalski
Jianshi
J
Yu
Victoria
V
Norman
Maureen A
MA
Kane
D000429:Alcohol Oxidoreductases / Q000378:metabolism; D000818:Animals; D005260:Female; D006706:Homeostasis; D008321:Mammary Glands, Animal / Q000378:metabolism*; D051379:Mice; D054840:Retinol-Binding Proteins, Cellular / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D014212:Tretinoin / Q000378:metabolism
C581954:CrbpI protein, mouse; C521400:Rbp7 protein, mouse; D054840:Retinol-Binding Proteins, Cellular; D014212:Tretinoin; D000429:Alcohol Oxidoreductases; C022520:retinol dehydrogenase