ID4 regulates mammary gland development by suppressing p38MAPK activity

Abstract

SUMMARYThe ID family of helix-loop-helix proteins regulates cell proliferation and differentiation in many different developmental pathways, but the functions of ID4 in mammary development are unknown. We report that mouse Id4 is expressed in cap cells, basal cells and in a subset of luminal epithelial cells, and that its targeted deletion impairs ductal expansion and branching morphogenesis as well as cell proliferation induced by estrogen and/or progesterone. We discover that p38MAPK is activated in Id4-null mammary cells. p38MAPK is also activated following siRNA-mediated Id4 knockdown in transformed mammary cells. This p38MAPK activation is required for the reduced proliferation and increased apoptosis in Id4-ablated mammary glands. Therefore, ID4 promotes mammary gland development by suppressing p38MAPK activity.KEY WORDS: ID4, p38MAPK (MAPK14, MAPK11), Mammary development, Breast cancer, Wnt, Mouse ID4 regulates mammary gland development by suppressing p38MAPK activity

ID4 controls luminal lineage commitment in normal mammary epithelium and inhibits BRCA1 function in basal-like breast cancer

“…The identity of these transcriptional regulators is currently unknown. Loss-of-function studies have confirmed the requirement for ID4 in ductal morphogenesis in the developing pubertal mammary gland (Dong et al 2011, Best et al 2014, Junankar et al 2015, with ID4-positive cells repopulating the adult mammary gland at a greater frequency than ID4-negative cells demonstrating the intrinsic stem cell activity of the ID4-positive basal cells (Junankar et al 2015). ID4-knockout mice also have delayed ductal morphogenesis further signifying the requirement for this transcription factor in mammary gland development (Dong et al 2011, Junankar et al 2015.…”

“…Similarly, ID4 is expressed in hormonally regulated tissues including the breast, ovaries and prostate and is required for normal development (Shan et al 2003, Dong et al 2011, Sharma et al 2013, Best et al 2014, Junankar et al 2015. ID4 is stimulated by progesterone receptor (PR) activity through direct binding of ligand-activated PR to the ID4 promoter (Fernandez-Valdivia et al 2008).…”

Dual roles for Id4 in the regulation of estrogen signaling in the mammary gland and ovary

“…Only 20% of mice survive on an Id4-null background, following a high proportion of embryonic and post-partum lethality resulting from severe brain and neuronal abnormalities (Bedford et al, 2005;Yun et al, 2004). In the male reproductive system, Id4 loss results in significantly reduced seminal vesicle size, prostatic intraepithelial neoplasia (PIN) lesions and sterility (Sharma et al, 2013), while a recent study in the mammary gland has shown that Id4 governs ductal elongation and branching via the Id4 target p38MAPK (Dong et al, 2011). In breast epithelial cells, Id4 negatively controls expression of the key tumor suppressor Brca1 (Beger et al, 2001) and also suppresses miR335, a positive regulator of Brca1 (Heyn et al, 2011).…”

Progesterone signalling in breast cancer: a neglected hormone coming into the limelight

“…In Wnt4 -/− and Id4 −/− (REF. 82) mammary epithelia side branching is delayed. The role of calcitonin awaits further studies.…”

“…Ectopic expression of its cousin WNT1 can rescue side branching by a paracrine mechanism in the absence of PR signalling 56 . Similarly, inhibitor of DNA binding 4 (ID4), a basic helix-loop-helix (bHLH) protein that is predominantly expressed in the myo epithelium is induced by progesterone, and its deletion in the mammary epithelium blocks side branching 82 . Calcitonin and amphiregulin have also been identified as in vivo progesterone targets 83 .…”