IRF6 in development and disease: A mediator of quiescence and differentiation

Abstract

Post utero development of the mammary gland is a complex developmental process characterized by states of rapid cell proliferation (branching morphogenesis) followed by functional differentiation (lactation) and the consequent apoptosis (involution) of the secretory mammary epithelial cell. This process is cyclical, such that involution returns the mammary gland to a near-virgin-like state capable of responding to morphogenic cues with each consecutive pregnancy. Importantly, many of the regulatory processes which oversee mammary gland development are corrupted or otherwise compromised during the development of breast cancer. For example, Interferon Regulatory Factor 6 (IRF6) is a novel protein with growth inhibitory properties that was initially identified in mammary epithelial cells through its interaction with maspin, a known tumor suppressor in normal breast tissue. Recent findings from our laboratory suggest that IRF6 functions synergistically with maspin to regulate mammary epithelial cell differentiation by acting on the cell cycle. This perspective focuses on the possible involvement of IRF6 in promoting differentiation by regulating exit from the cell cycle and entry into the G(0) phase of cellular quiescence, and how these new findings shed light on normal mammary gland development and the initiation and progression of breast cancer.

p63 and IRF6: brothers in arms against cleft palate

“…Recent advances (19) provide hope that direct targets of IRF6 can be identified and then assessed as potential causal genes in orofacial clefting. Since p63 and IRF6 are known to be involved in cancer (1,8,15) and in view of the present findings (9, 10), it wouldn't be surprising if the p63-IRF6 relationship were disrupted in cancer, albeit with variation inherent to neoplasia.…”

“…TGF-β signaling exerts roles in tumor suppression and metastasis, and recent findings point to a tumor suppressor function for p63, which promotes the oncogenic function of TGF-β in cancer cells when it is lost subsequent to its TGF-β-dependent sequestration by mutant p53 (15). IRF6 mRNA and protein are totally lost in metastatic breast cancer cell lines and in invasive breast ductal carcinomas (8). These observations suggest that TGF-β, p63, and IRF6 also interact in cancer.…”

“…Compound heterozygous Sumo1 +/-p63 +/-mice may prove informative in this regard. IRF6 is also a substrate for proteasomal degradation, following phosphorylation and ubiquitination (8); however, the molecular mechanisms behind its posttranslational modification are still unknown. How does the IRF6-p63 regulatory loop integrate into other signaling pathways under normal and diseased states?…”

“…The discovery that mutations in the genes encoding p63 and IRF6 cause human ectodermal dysplasia syndromes triggered a chain reaction of research aimed at unravelling their functions and identifying their targets during normal and abnormal epithelial development (4)(5)(6)(7)(8). Yet, their mode of action, regulation, and targets during normal lip and palate development and the mechanisms behind the genesis of CL/CP in both humans and mouse models are still largely unknown.…”

Exosomes, endogenous retroviruses and toll-like receptors: pregnancy recognition in ewes

“…In previous analyses, IRF6 was hypothesized to promote proliferation and development of the placenta (Fleming et al 2009). However, recent results have suggested that IRF6 functions synergistically with maspin to induce differentiation of epithelial cells by regulating exit from the cell cycle and entry into the G(0) phase of cellular quiescence (Bailey & Hendrix 2008, Biggs et al 2014.…”