Tumor Type-Dependent Function of the Par3 Polarity Protein in Skin Tumorigenesis

Abstract

Cell polarization is crucial during development and tissue homeostasis and is regulated by conserved proteins of the Scribble, Crumbs, and Par complexes. In mouse skin tumorigenesis, Par3 deficiency results in reduced papilloma formation and growth. Par3 mediates its tumor-promoting activity through regulation of growth and survival, since Par3 deletion increases apoptosis and reduces growth in vivo and in vitro. In contrast, Par3-deficient mice are predisposed to formation of keratoacanthomas, cutaneous tumors thought to originate from different cellular origin and frequently observed in humans. Par3 expression is reduced in both mouse and human keratoacanthomas, indicating tumor-suppressive properties of Par3. Our results identify a dual function of Par3 in skin cancer, with both pro-oncogenic and tumor-suppressive activity depending on the tumor type.

Loss of the Polarity Protein PAR3 Activates STAT3 Signaling via an Atypical Protein Kinase C (aPKC)/NF-κB/Interleukin-6 (IL-6) Axis in Mouse Mammary Cells

“…The present study confirms our prior report that loss of PAR3 activates aPKC in mouse mammary epithelial cells (15). The mislocalization of apical aPKC enrichment following PAR3 silencing has been described previously both by us (15) and others (16,18). Therefore, we propose that the loss of PAR3 enables the inappropriate interaction of active aPKC with signaling networks, such as NF-B, in mammary cells.…”

“…Loss of PAR3 leads to the mislocalization of aPKC in epithelial cells (15)(16)(17)(18), accompanied in some contexts by activation (15). This observation, combined with evidence that aPKC/ has oncogenic functions (21), indicates that inappropriate aPKC/ activation may favor tumor aggression when PAR3 is silenced.…”

“…Expression of the Notch-1 intracellular domain (NICD1) oncogene alone does not induce STAT3 in mouse mammary cells (mMECs) (15), showing that the effect depends on loss of PAR3. Moreover, NICD1-transformed mMECs (NICD1-mMECs) properly localize polarity markers, such as aPKC, but these markers become disrupted when PAR3 is silenced (15), recapitulating what is observed in other epithelial cells (16,18).…”

“…This observation, combined with evidence that aPKC/ has oncogenic functions (21), indicates that inappropriate aPKC/ activation may favor tumor aggression when PAR3 is silenced. Although the literature suggests several mechanisms by which aPKC activation could promote STAT3 signaling, such as potentiating TNF-␣ signaling (22), interacting with NF-B (23), promoting ERK activity (24,25), and transducing signals downstream of EGFR or RAS (16,26,27), it is not obvious which is involved when PAR3 expression is disrupted. In the present study, we use gene silencing to rigorously test the role of aPKC/ following Pard3 knockdown in transformed mouse mammary cells and to identify the mechanism through which it induces STAT3.…”

AmotL2 disrupts apical–basal cell polarity and promotes tumour invasion

“…Par3 is frequently lost in human cancer, and genetic deletion of Par3 may predispose mice to the formation of breast and skin tumours 14,31,32 . We therefore investigated whether retention in vesicles would alter the functionality of Par3 molecules.…”