Abstract PR01: Loss of the hippo pathway scaffold “Kibra” in a mouse model of human claudin-low breast cancer
Bibliographic record
Abstract
Abstract Human claudin-low breast cancers belong to the triple negative subclass of the disease. Triple negative breast cancers (TNBCs) cannot be treated with targeted therapies that exist for estrogen receptor and Her2-positive breast cancers, emphasizing the need for new therapeutic targets. We generated a mouse model which recapitulates key features of the claudin-low subtype (Knight et al., PNAS 2013). In this model, expression of the Met receptor tyrosine kinase synergizes with loss of the tumor suppressor gene p53 (MMTV-Met;Trp53fl/+;MMTV-Cre) in driving mammary tumorigenesis. MMTV-Met;Trp53fl/+;Cre mammary tumors have a predominately spindloid pathology, with low expression of cell junction molecules and epithelial markers, and high expression of an epithelial-to-mesenchymal transition (EMT) signature. Use of array-CGH to assess the genomic landscape of MMTV-Met;Trp53fl/+;Cre claudin-low tumors identified amplification of the endogenous Met locus, suggestive of oncogene addiction. Consistent with this, primary cells derived from these tumors were dependent upon Met signaling for proliferation and survival. Furthermore, Met inhibition in these cells was able to partially restore cell-cell junctions. In addition to Met amplification, a consistent genomic event in MMTV-Met;Trp53fl/+;Cre tumors was loss of a chromosome 11 region, syntenic with human chromosome 5q, loss of which is a frequent event in human TNBC. Located within this region is the gene Wwc1, also known as Kibra, which encodes a scaffold protein known to positively regulate the Hippo tumor suppressor pathway. To understand the contribution of Kibra loss to claudin-low biology, we performed Kibra RNA interference in MMTV-Met (wildtype p53) solid carcinoma cells, in which Kibra expression is retained. Knockdown of Kibra led to weakening of cell-cell junctions and colony dispersal, consistent with EMT induction. This work supports that Kibra loss and consequential disruption of the Hippo pathway, may play a significant role in claudin-low biology. Our work now focuses on re-induction of Hippo signaling in human and mouse claudin-low tumor cells to increase our understanding of the role of this pathway in tumor promotion and to provide new possibilities for therapeutic intervention in TNBCs. This abstract is also presented as Poster A010. Citation Format: Jennifer F. Knight, Robert Lesurf, Sadiq M. Saleh, Ryan R. Davis, Hong Zhao, Dongmei Zuo, Robert D. Cardiff, Jeff Gregg, Michael Hallett, Morag Park. Loss of the hippo pathway scaffold “Kibra” in a mouse model of human claudin-low breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr PR01.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".