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

Filippone et al. show that the frequent activation of PKCs leads to aberrant phosphorylation of the tumor suppressor Numb in breast cancer. Aberrantly phosphorylated Numb fails to determine asymmetric cell division, resulting in expansion of the cancer stem cell compartment, associated with an aggressive disease course. Asymmetric cell division is a key tumor suppressor mechanism that prevents the uncontrolled expansion of the stem cell (SC) compartment by generating daughter cells with alternative fates: one retains SC identity and enters quiescence and the other becomes a rapidly proliferating and differentiating progenitor. A critical player in this process is Numb, which partitions asymmetrically at SC mitosis and inflicts different proliferative and differentiative fates in the two daughters. Here, we show that asymmetric Numb partitioning per se is insufficient for the proper control of mammary SC dynamics, with differential phosphorylation and functional inactivation of Numb in the two progeny also required. The asymmetric phosphorylation/inactivation of Numb in the progenitor is mediated by the atypical PKC zeta isoform. This mechanism is subverted in breast cancer via aberrant activation of PKCs that phosphorylate Numb in both progenies, leading to symmetric division and expansion of the cancer SC compartment, associated with aggressive disease. Thus, Numb phosphorylation represents a target for breast cancer therapy.

Automated summary

Filippone et al. demonstrate that the frequent activation of PKCs in breast cancer leads to abnormal phosphorylation of the tumor suppressor Numb. Aberrantly phosphorylated Numb affects asymmetric cell division, resulting in expansion of cancer stem cell compartment and aggressive disease course. Asymmetric cell division, controlled by Numb, plays a critical role in preventing uncontrolled expansion of the stem cell compartment. However, in breast cancer, aberrant PKC activation phosphorylates Numb in both progeny, leading to symmetric division and expansion of cancer stem cells.