Elucidating the Transcriptional Regulatory Roles of STAT3 and FOXA1 Transcription Factors in Genetically Engineered Mouse Models of Human Breast Cancer
Bibliographic record
Abstract
Breast cancer is the predominant cancer type among Canadian women, with a striking incidence rate of one in eight women during their lifetime. Transcription factors play pivotal roles in breast cancer initiation and progression. Signal transducer and activator of transcription 3 (Stat3) is a transcription factor that mediates the expression of a variety of genes in response to cytokines and growth factors. The activation of Stat3 plays key roles in cell growth, survival and apoptosis, cell migration and invasion, and inflammation. Using the conditional Stat3 knockout mouse model, our lab previously demonstrated that Stat3 deficiency can impede the metastasis of ErbB2-positive breast cancer. However, the mechanism remains unclear. By doing transcriptomic analysis of Stat3-null and wildtype ErbB2 positive breast cancer cells dissociated from mouse tumors, Lgals3 turned out to be a target of Stat3 that could have mediated the metastatic phenotype. Upon shRNA knockdown of Lgals3, ErbB2 positive breast cancer cells demonstrated dramatically reduced migration and invasion. They also formed elevated levels of focal adhesions that may lead to reduced migration and metastasis. Furthermore, the pharmacological inhibition of Gal-3 leads to decreased cell migration and invasion. This reveals the therapeutic potential of Lgals3 inhibition in ErbB2-Positive breast cancer metastasis prevention. Estrogen receptor (ER) positive breast cancer accounts for about 70% of total breast cancer and metastatic ER-Positive breast cancer accounts for the majority of breast cancer mortality. Although ER-Positive breast cancer is the most common subtype of breast cancer, there is a lack of mouse models that faithfully recapitulate ER-driven breast cancer. Published research from our lab has shown that knock-in mutation of ESR1Y541S results in constitutive activation of ER, abnormal mammary gland development, male mouse feminization, and decreased survival, but no tumor growth is associated with this mouse model. Forkhead box protein A1 (FOXA1) is a transcription factor that facilitates ER-chromatin association, and promotes tumorigenesis through a variety of mechanisms. By overexpressing FOXA1 in the doxycycline-inducible mouse model named FIC/MTB and crossing it to ESR1 mouse model (FIC/MTB/ESR1), we may be able to create a novel ER-Positive breast cancer mouse model. We demonstrated that FIC/MTB mouse mammary gland-derived organoids developed a filled sphere structure upon doxycycline induction, mimicking human mammary gland hyperplasia. Moreover, the FIC/MTB/ESR1 mice developed significant hyperplasia after 20-week induction. Although in vivo tumor kinetics study is ongoing, our current findings suggest that the novel mouse model FIC/MTB/ESR1 has the potential to develop mammary tumors
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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 | 0.000 | 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".