Abstract LB-93: The role of GSK-3 in mammary gland development and oncogenesis
Bibliographic record
Abstract
Abstract Glycogen synthase kinase 3, comprised of two isoforms: α and β, is a central regulator of several signaling pathways that play key roles in development and cancer. Chemical inhibition or genetic loss of GSK-3 in a normal mouse breast cell line cultured under conditions resembling the physiological breast environment resulted in morphological defects reminiscent of early stages of disease. A similar phenotype was also observed upon expression of an activated allele of β-catenin, a major GSK-3 target protein often mutated and elevated in human cancers. These findings implicate GSK-3 as a key regulator of normal ductal development, which may be disrupted early in cancer progression. Upon genetic deletion of GSK-3 (double knock-out of all four alleles, DKO) from breast tissues of mice, dams are unable to nurse their pups. These animals develop severe mammary intraepithelial neoplasia and squamous metaplasia frequently at first pregnancy. Following 4–6 months of continuous breeding, breast adenocarcinomas are observed with elevated levels of ß-catenin and Gli, along with increased expression of a putative mammary progenitor cell marker. Increased cell growth as well as expression of smooth muscle actin, a myoepithelial marker, are also features of these tumors. Similar developmental and functional defects are also observed in mice with breast glands lacking GSK-3 as well as ß-catenin (triple knock-out, TKO). The epithelium of TKO mammary glands undergoes various degrees of squamous differentiation and keratinization, although at a lower penetrance than the DKOs. Multiparious TKOs develop tumors, albeit with a longer latency (7–9 months). Preliminary flow cytometry analysis of mammary glands from DKO and TKO animals show the ratio of luminal to basal cell populations is increased in absence of GSK-3. We are currently investigating how GSK-3 may regulate mammary stem/progenitor cell commitment to these mammary cell lineages. Previously reported expression of stabilized ß-catenin in the mammary epithelium induces squamous metaplasia, but no adenocarcinomas were observed at 6 months. In our hands, these animals do develop small tumors at ∼10 months of age. These data suggest the observed DKO and TKO phenotypes are not solely mediated via aberrant ß-catenin signaling and that GSK-3 has ß-catenin-independent functions in mammary gland disease. Other pathways regulated by GSK-3 including Notch, Hedgehog and PI3K are being interrogated in DKO and TKO tumor-initiating cells to gain a molecular understanding of tumor development. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-93. doi:10.1158/1538-7445.AM2011-LB-93
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.002 |
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 source (direct Gemma or distilled Codex), 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".