A molecular landscape of quiescence/proliferation highlights the role of Pten in mammary gland acinogenesis.

Cell context is key for cell state. Using physiologically relevant models of laminin-rich ECM (lrECM) induction of mammary epithelial cell quiescence and differentiation, we provided a landscape of the key molecules for the proliferation/quiescence decision, with multiple layers of regulation at the mRNA and protein levels. Quiescence occurred despite active Fak, Src and PI3k, suggesting the existence of a disconnecting node between upstream and downstream proliferative signalling. Pten, a lipid and protein phosphatase, fulfils this role because its inhibition increased proliferation and restored Akt/mTORC1/2 and Mapk signalling. Pten and laminin levels were positively correlated in murine developing mammary epithelia and Pten localized to apicolaterally in luminal cells in ducts and near the nascent lumen in terminal end buds. Consistently, in 3D acinogenesis models, Pten was required for triggering and sustaining quiescence, polarity and architecture. The multilayered regulatory circuitry that we uncovered provides an explanation for the robustness of quiescence within a growth-suppressive microenvironment, which could nonetheless be disrupted by perturbations in master regulators, such as Pten.