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Pten is a disconnecting node in the molecular landscape of the proliferation/quiescence decision during mammary gland acinogenesis

Rebeka Tomasin,A. Rodrigues,A. C. Manucci,A. Bruni-Cardoso

Published 2023 in bioRxiv

ABSTRACT

Cell context is key for cell phenotype. Using physiologically relevant models of laminin-rich ECM (lrECM) induction of mammary epithelial cell quiescence and differentiation, we have provided a landscape of the status of key molecular players involved in the proliferation/quiescence decision. Repression of some positive regulators of the cell cycle, such as cyclins and CDKs, occurred already at the mRNA level, whereas negative regulators of the cell cycle, such as Pten and p27, were upregulated only at the protein level. Interestingly, cell cycle arrest occurred despite the active status of Fak, Src and PI3k, because their downstream proliferative signalling pathways were repressed, suggesting the existence of a disconnecting node between upstream and downstream proliferative signalling in quiescent cells. Pten fulfils this role. Inhibition of Pten increased proliferation and restored Akt/mTORC1/2 and Mapk signalling in cells exposed to lrECM. In mice, Pten levels were positively correlated to the basement membrane thickness in the developing mammary epithelia, and Pten localized to the apicolateral membrane of luminal cells both in in ducts and near the nascent lumen in terminal end bud, characteristics consistent with a role for Pten in inducing and sustaining quiescence and tissue architecture. Accordingly, in 3D acininogenesis models, Pten was required for the onset and maintenance of quiescence, cell polarity and lumen assembly. The notion that lrECM-triggered differentiation involves a signalling circuitry with many layers of regulation provides an explanation for the resilience of quiescence within a growth-suppressive microenvironment, and that perturbations in master regulators, such as Pten, could disrupt the quiescent phenotype.

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