Hippo inactivation feeds tumor-initiating cells

The Hippo pathway has emerged as a well-conserved kinase cascade controlling cell proliferation and survival and has recently gained much attention for its key activity as a tumor suppressor. In a study published in Cell, Cordenonsi and colleagues link TAZ, a downstream effector of the Hippo pathway, to attributes of putative breast cancer stem cells, epithelial-to-mesenchymal transition and cell polarity.

Whereas many upstream components of the Hippo pathway in Drosophila [10] and zebrafi sh [11] have been identifi ed, those in mammals remain poorly defi ned. Th e work of Cordenonsi and colleagues [12] indicates a role for EMT and the polarity gatekeeper Scribble upstream of the Hippo cascade in human breast tumor-initiating cells.

The article
To identify signaling pathways that drive breast tumorigenesis and heterogeneity, Cordenonsi and colleagues [12] analyzed a gene expression metadataset of breast tumors and found a TAZ/YAP signature to be correlated with high-grade (poorly diff erentiated) tumors. Th ese tumors were previously shown to express embryonic and mammary stem cell signatures. Immuno histochemistry further revealed that TAZ is over ex pressed in high-grade tumors, in part due to the amplifi cation of the TAZencoding locus. Th e authors found that constitutive knockdown of TAZ in Ras-transformed MCF10A breast cancer models decreases tumorsphere formation capacity, the number of cells with the cancer stem cell phenotype (CD44 High CD24 low ), and tumorigenic potential. Expression of an activated mutant of TAZ in breast cancer cells increased the number of cells with the cancer stem cell phenotype, tumorsphere forming capacity, resistance to taxol, and the number of tumor-initiating cells.
Th e authors further assessed the relationship between EMT, tumorsphere formation and TAZ. Th ey confi rmed previous results showing that overexpression of TAZ induces EMT [6,9]. Th ey also found that EMT increases TAZ protein expression and, notably, that TAZ increases tumorsphere formation independently of the loss of Ecadherin. Moreover, even though TAZ is a critical mediator of tumorsphere formation downstream of EMT, its inhibition was not suffi cient for reversion of the EMT phenotype.
But how does EMT regulate TAZ? Scribble, a gatekeeper of epithelial cell polarity, is an upstream component of the Hippo pathway in zebrafi sh [11]. In breast cancer cells, Cordenonsi and colleagues were able to show that Scribble is essential for the nucleation of a complex of TAZ, LATS and MST. In particular, EMT causes delocalization of Scribble from the cell membrane,

Abstract
The Hippo pathway has emerged as a well-conserved kinase cascade controlling cell proliferation and survival and has recently gained much attention for its key activity as a tumor suppressor. In a study published in Cell, Cordenonsi and colleagues link TAZ, a downstream eff ector of the Hippo pathway, to attributes of putative breast cancer stem cells, epithelial-to-mesenchymal transition and cell polarity.

The viewpoint
Th e paper by Cordenonsi and colleagues links Hippo signaling to EMT, cell polarity, tumorsphere formation, the cancer stem cell phenotype, and tumor-initiating cells. Th e fact that inactivation of Hippo signaling is crucial for a tumorigenic subpopulation of breast cancer cells raises the possibility that therapeutic activation of Hippo signaling or blockade of its downstream eff ectors could improve current treatment strategies. Th is is further underscored by the potent oncogenic activity of YAP in diff erent preclinical cancer models and by the loss of function of LATS1/2 kinases in breast tumors [4].
Th e induction of metastases by TAZ activation was not reported by Cordenonsi and colleagues and warrants further investigation. It would also be important to address whether TAZ knockdown after overt tumor forma tion reduces tumor growth and progression.
Research in mammals is defi ning the upstream components of the Hippo pathway and some of them are linked to cell polarity, cell adhesion, and cell junction proteins [13]. Th e work of Cordenonsi and colleagues now adds Scribble to the list of mammalian upstream Hippo pathway components. Signifi cantly, depletion of Scribble in breast cells was shown previously to disrupt cell polarity, block three-dimensional morphogenesis, inhibit apoptosis, and induce dysplasia in vivo [14]. Other Hippo pathway upstream components such as NF2 (neurofi bromin 2, merlin) [15,16], CD44 [15], the CRB (crumbs homolog) polarity complex [17], and the Ecadherin-catenin adhesion complex [18] also infl uence TAZ/YAP activity and EMT. For example, the CRB complex regulates TAZ/YAP and its disruption enhances transforming growth factor-beta signaling and activates SMAD-dependent transcription, which induces markers of EMT [17]. Hopefully, ongoing investigations will elucidate the interplay of these pathway components and identify specifi c upstream activators as well as downstream eff ectors in normal and neoplastic breast. Th ese eff orts should lead ultimately to the identifi cation of novel targets for therapy.