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    • Department of Developmental Biology & Genetics (DBG, earlier called MRDG)
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    Investigating the role of AMPK in mammary gland alveologenesis and lactation

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    Author
    Lal, Shyam
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    Abstract
    AMP-activated kinase (AMPK) is an energy sensor that regulates cell growth and metabolism. Reports from our laboratory and others have shown the context-specific role of AMPK signaling in breast cancer. However, its role in normal mammary gland growth and function is unclear. Here, we showed that AMPK expression and activity within murine mammary epithelia increased from puberty to pregnancy, reaching its highest levels during lactation, and then declined post-lactation. Further, induction of prolactin (PRL) signaling increased AMPK expression and activity in ex vivo organotypic cultures of mammary epithelial cells (MECs), whereas PRL failed to do so in 2D monolayer culture of MECs. To understand the role of AMPK in mammary gland morphogenesis in vivo, we generated mice with conditional knockout of the catalytic AMPK isoforms 1 and 2 (AMPK⍺1,⍺2 homo cDKO) in mammary gland. Whole mount analysis of AMPK⍺1,⍺2 homo cDKO mammary glands demonstrated precocious alveolar development with increased epithelial content due to enhanced proliferation and altered differentiation. This was corroborated by ex vivo organotypic cultures wherein pharmacological inhibition of AMPK in primary MECs led to the formation of bigger acini with a significantly increased number of cells AMPK⍺1,⍺2 homo cDKO mice also showed increased beta-casein expression with significantly increased pups’ weight when compared with wild-type control mice. Interestingly, AMPK⍺1,⍺2 homo cDKO epithelia showed increased phosphorylated STAT5 which is known to drive alveologenesis downstream of PRL signaling, suggesting a negative correlation between the two pathways. Interestingly, Akt inhibition led to reversal of phenotype in AMPK⍺1,⍺2 homo cDKO MECs cultured in 3D LrECM, demonstrating a negative cross talk between AMPK and Akt in maintaining cellular homeostasis during alveolar morphogenesis. Our study thus identifies a novel interplay between AMPK and Akt that determines mammary alveologenesis and differentiation through PRL-JAK2-STAT5 signaling.
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    https://etd.iisc.ac.in/handle/2005/6119
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    • Department of Developmental Biology & Genetics (DBG, earlier called MRDG) [151]

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