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Aberrant phosphorylation inactivates Numb in breast cancer causing expansion of the stem cell pool

Maria Grazia Filippone1, Stefano Freddi1, Silvia Zecchini1

  • 1IEO-IRCCS, Istituto Europeo di Oncologia-Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy.

The Journal of Cell Biology
|October 6, 2022
PubMed

Insights

Asymmetric cell division relies on Numb protein partitioning and differential phosphorylation for mammary stem cell regulation. Aberrant Numb phosphorylation in cancer drives uncontrolled stem cell expansion and aggressive disease.

Area of Science:

  • Cell Biology
  • Cancer Biology
  • Stem Cell Biology

Background:

  • Asymmetric cell division is crucial for preventing stem cell (SC) overexpansion.
  • Numb protein plays a key role in directing daughter cell fates during SC division.

Purpose of the Study:

  • To investigate the role of Numb partitioning and phosphorylation in mammary stem cell (SC) dynamics.
  • To elucidate the mechanism of Numb regulation by protein kinase C (PKC) isoforms.
  • To understand how this mechanism is altered in breast cancer.

Main Methods:

  • Studied asymmetric Numb partitioning during mammary stem cell mitosis.
  • Investigated the role of differential Numb phosphorylation in daughter cell fate determination.
  • Analyzed the involvement of atypical PKCζ in Numb inactivation.
  • Examined aberrant PKC activation in breast cancer stem cells.

Main Results:

  • Asymmetric Numb partitioning alone is insufficient for controlling mammary SC dynamics.
  • Differential phosphorylation and functional inactivation of Numb are essential.
  • Atypical PKCζ mediates asymmetric Numb phosphorylation/inactivation in progenitor cells.
  • Aberrant PKC activation in breast cancer leads to symmetric division and cancer SC expansion.

Conclusions:

  • Proper mammary SC regulation requires both asymmetric Numb partitioning and differential phosphorylation.
  • PKC-mediated Numb phosphorylation is a critical control point.
  • Subversion of this mechanism by aberrant PKCs contributes to breast cancer progression.
  • Targeting Numb phosphorylation offers a potential therapeutic strategy for breast cancer.

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