Fatty acid amide hydrolase drives adult mammary gland development by promoting luminal cell differentiation

Mammary gland development occurs primarily in the adult, undergoing extensive expansion during puberty followed by cycles of functional specialization and regression with every round of pregnancy/lactation/involution. This process is ultimately driven by the coordinated proliferation and differentiation of mammary epithelial cells, but the endogenous factors regulating these developmental dynamics are still poorly defined. Endocannabinoid signaling is known to determine cell fate-related events involved in the development of different organs in the central nervous system and the periphery. Here, we report that the endocannabinoid-degrading enzyme fatty acid amide hydrolase (FAAH) plays a pivotal role in adult mammary gland development. Specifically, it is required for luminal lineage specification in the mammary gland, and it promotes hormone-driven secretory differentiation of mammary epithelial cells by controlling the endogenous levels of anandamide and the subsequent activation of CB1R. Together, our results shed some light on the role of the endocannabinoid system in breast development and introduce FAAH-signaling as a new therapeutic target in milk production deficits.

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