Reciprocal Intra-Epithelial Interactions between TP63 and Hedgehog Signaling Regulate Quiescence and Activation of Progenitor Elaboration by Mammary Stem Cells

¹ Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire 03755 USA
² Department of Medicine, Massachusetts General Hospital Center for Cancer Research and Harvard Medical School, Boston, Massachusetts 02114, USA
³ Department of Genetic Medicine, Weill Cornell Medical College, New York 10021, USA

^* To whom correspondence should be addressed. E-mail: james.direnzo{at}dartmouth.edu.

	Abstract

TP63 is required for preservation of epithelial regenerative stasis and regulates the activity of diverse genetic pathways, however specific effecter pathways are poorly understood. Data presented here indicate that reciprocal regulatory interactions between hedgehog signaling and TP63 mediate stage-specific effects on proliferation and clonigenicity of separable enriched mammary stem and progenitor fractions. Analysis of N-p63 and TA-p63 indicates segregated expression in mammary stem and progenitor fractions respectively, demonstrating that differential TP63 promoter selection occurs during elaboration of mammary progenitors by mammary stem cells. This segregation underlies mammary progenitor-specific expression of Indian Hedgehog, identifying it as a binary transcriptional target of TP63. Hedgehog activation in vivo enhances elaboration of mammary progenitors and decreases label-retention within mammary stem cell-enriched fractions, suggesting that hedgehog exerts a mitogenic effect on mammary stem cells. Hedgehog signaling promotes differential TP63 promoter usage via disruption of Gli3 or Gli3^R accumulation and shRNA-mediated disruption of Gli3 expression was sufficient to alter TP63 promoter usage and enhance clonigenicity of mammary stem cells. Finally, hedgehog signaling is enhanced during pregnancy where it contributes to expansion of the mammary progenitor compartment. These studies support a model in which hedgehog activates elaboration and differentiation of mammary progenitors via differential TP63 promoter selection and forfeiture of self-renewing capacity.

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