Polarity matters: the Par6 pathway and the dual role of transforming growth factor-beta in breast cancer progression
Apico-basal polarity is essential for epithelial tissue homeostasis and epithelial malignant transformation is accompanied by progressive loss of apico-basal polarity. The epithelialmesenchymal transition (EMT), a phenomenon of cellular plasticity characterized by the loss of epithelial features and the acquisition of mesenchymal traits, is a well-documented
mechanism of polarity loss in epithelial tumors, particularly in breast cancer.
Transforming growth factor-beta (TGFβ) is a potent inducer of EMT in mammary cells, and EMT has been proposed as one of the mechanisms by which TGFβ promotes invasion and metastasis of breast tumors. Interestingly, TGFβ also suppresses the growth of breast tumors at early stages of tumor progression, in part by inducing cell death. This dual capacity of TGFβ to act as a tumor suppressor at early stages and as a promoter of metastasis at later stages of breast cancer progression has been the focus of research for several decades, and it continues to be a matter of debate whether or not TGFβ will prove to be a good target for breast cancer therapy.
A non-canonical TGFβ signaling pathway referred to as “the Par6 polarity pathway” was initially identified in 2005 as an essential mediator of TGFβ-induced loss of apical-basal polarity and EMT. As its name indicates, this pathway is mediated by Par6, a core component of the Par complex that localizes to the epithelial tight junction (TJ) and is essential for the establishment of apico-basal polarity. Par6 phosphorylation by the TGFβ
receptor activates a cascade of events that culminate with the issolution of the TJ and rearrangement of the actin cytoskeleton, which favors a mesenchymal-like morphology.
Here we present evidence of the role of the TGFβ-Par6 pathway on the dual function of TGFβ. Using immortalized and transformed mammary cell lines, and a combination of three-dimensional cultures and animal models, we have demonstrated that the Par6 pathway drives loss of apico-basal polarity, EMT and mammary carcinoma metastasis. Importantly, Par6 activation promotes morphological changes that are independent of the transcriptional gene program classically activated by the canonical Smad pathway, and thus these two pathways are complementary and are both necessary for EMT to occur.
More recently we have also found that in immortalized mammary cells in which apicalbasal polarity is compromised, the Par6 and Smad pathways cooperate in promoting cell death, and an overactive Par6 pathway significantly enhances cell death in response to TGFβ. Our observations also indicate that Par6 overexpression and overactivity negatively modulate PI3K/Akt and NF-κB in response to long- term TGFβ exposure, and suggest that PI3K modulation downstream of Par6 might be key in determining whether a cell dies or survive in response to TGFβ. Based on this, we propose strategies to rescue TGFβ tumor suppressive function in advanced breast tumors, which we believe might prove beneficial for treating specific subtypes of breast cancer.