Abstract
BackgroundThe oncoprotein c-Myc has been intensely studied in breast cancer and mouse mammary tumor models, but relatively little is known about the normal physiological role of c-Myc in the mammary gland. Here we investigated functions of c-Myc during mouse mammary gland development using a conditional knockout approach.ResultsGeneration of c-mycfl/fl mice carrying the mammary gland-specific WAPiCre transgene resulted in c-Myc loss in alveolar epithelial cells starting in mid-pregnancy. Three major phenotypes were observed in glands of mutant mice. First, c-Myc-deficient alveolar cells had a slower proliferative response at the start of pregnancy, causing a delay but not a block of alveolar development. Second, while milk composition was comparable between wild type and mutant animals, milk production was reduced in mutant glands, leading to slower pup weight-gain. Electron microscopy and polysome fractionation revealed a general decrease in translational efficiency. Furthermore, analysis of mRNA distribution along the polysome gradient demonstrated that this effect was specific for mRNAs whose protein products are involved in milk synthesis. Moreover, quantitative reverse transcription-polymerase chain reaction analysis revealed decreased levels of ribosomal RNAs and ribosomal protein-encoding mRNAs in mutant glands. Third, using the mammary transplantation technique to functionally identify alveolar progenitor cells, we observed that the mutant epithelium has a reduced ability to repopulate the gland when transplanted into NOD/SCID recipients.ConclusionWe have demonstrated that c-Myc plays multiple roles in the mouse mammary gland during pregnancy and lactation. c-Myc loss delayed, but did not block proliferation and differentiation in pregnancy. During lactation, lower levels of ribosomal RNAs and proteins were present and translation was generally decreased in mutant glands. Finally, the transplantation studies suggest a role for c-Myc in progenitor cell proliferation and/or survival.See related minireview by Evan et al:
Highlights
The oncoprotein c-Myc has been intensely studied in breast cancer and mouse mammary tumor models, but relatively little is known about the normal physiological role of c-Myc in the mammary gland
WAPiCre-mediated ablation of c-Myc in the mammary gland To study the role of c-Myc in mammary gland development, we used a conditional approach, crossing c-mycfl/fl mice [21] to WAPiCre transgenic mice [35]
Since the half-life of c-Myc protein and mRNA is short [37], it is likely that mutant glands have little or no c-Myc by the onset of lactation
Summary
The oncoprotein c-Myc has been intensely studied in breast cancer and mouse mammary tumor models, but relatively little is known about the normal physiological role of c-Myc in the mammary gland. C-Myc stimulates RNA Pol I [6,7] and Pol III [8,9] mediated transcription, linking it to ribosome biogenesis and translation. At the start of pregnancy, c-Myc-deficient alveolar cells were impeded in their proliferative response resulting in a delayed ability to differentiate. Mutant glands displayed lower expression levels of ribosomal RNA and proteins as well as a general decrease in translation. The mutant mammary epithelium had a reduced ability to grow when transplanted into mammary fat pads. These results suggest that c-Myc has multiple roles in the mammary gland, affecting proliferation, biosynthetic capacity, and progenitor cell proliferation and/or survival
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