Abstract P4-05-02: Conditional inactivation of the 25-hydroxyvitamin D-24-hydroxylase (Cyp24a1) in the mouse mammary epithelium alters mammary gland development
Bibliographic record
Abstract
Abstract The biologically active form of vitamin D (1,25(OH)2D) regulates proliferation, differentiation, and apoptosis in diverse cell types. We have previously identified anti-proliferative activities of 1,25(OH)2D in human breast tissue, as well as 1,25(OH)2D target gene expression consistent with reports that elevated vitamin D levels may protect against cancer. In mouse studies, vitamin D signaling modulates normal mammary gland development, including ductal outgrowth and branching, and protects against tumorigenesis. Degradation of 1,25(OH)2D is initiated by the enzyme Cyp24a1 in target tissues, providing critical local control of 1,25(OH)2D bioactivity. In vitro, blockade of Cyp24a1 activity potentiates the anti-proliferative effects of 1,25(OH)2D. However, the extent to which endogenous Cyp24a1 activity within the mammary epithelium regulates local 1,25(OH)2D levels to modulate normal mammary gland development, with possible implications for cancer, has not been investigated. We generated a novel mouse model with conditional knockout of the Cyp24a1 gene specifically in the mammary epithelium (MMTV-Cre x Cyp24a1lox/lox). Ablation of Cyp24a1 activity in the mammary epithelium does not alter either gland or body weight at 4, 6 or 10 weeks of age. Preliminary analyses of mammary gland whole mounts indicate that virgin knockout mice form fewer terminal end buds compared to glands from wild-type littermates at 4 and 6 weeks of age (P<0.05). Moreover, the width of the ducts proximal to the central lymph node of knockout mice was less than that of wild-type mice at 4 and 10 weeks of age (P<0.05 and P<0.01, respectively). In addition, the number of secondary and tertiary branching points is reduced in mammary glands from knockout mice at 6 weeks of age (P<0.05 and P<0.01, respectively). In summary, our findings suggest that Cyp24a1 activity within epithelial cells plays a crucial role to modulate postnatal mammary gland development, presumably by limiting the local accumulation of 1,25(OH)2D. Citation Format: Sheng L, Turner AG, Tarulli GA, Barratt K, Kremer R, Morris HA, Callen DF, Anderson PH. Conditional inactivation of the 25-hydroxyvitamin D-24-hydroxylase (Cyp24a1) in the mouse mammary epithelium alters mammary gland development [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-05-02.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.002 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.002 | 0.003 |
| Insufficient payload (model declined to judge) | 0.011 | 0.004 |
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".