Abstract P5-11-04: Inhibition of alternative NF-κB activity prevents the expansion of genetically unstable progenitor cells in BRCA1-deficient mammary glands
Bibliographic record
Abstract
Abstract Understanding the biological mechanisms underlying the initiation and progression of breast cancer is an important step for prevention and treatment. Individuals with mutations in the breast cancer-associated gene 1 (BRCA1) have a lifetime increased risk of up to 85% of developing breast cancer. BRCA1 participates in DNA damage repair and cell cycle checkpoint control, serving as a tumor suppressor gene to maintain global genomic stability. However, BRCA1 has also been shown to play a key role in the expansion of mammary stem/progenitor cells, which are the targets for carcinogenesis in individuals who have undergone loss of heterozygosity (LOH) for BRCA1. We have used in vitro and in vivo models to demonstrate that BRCA1 loss or mutation induces alternative NF-κB pathway activation and leads to the expansion of a genetically unstable progenitor cell population in the mammary gland. Our data showed that BRCA1 loss or mutation is responsible for activation of the alternative NF-κB pathway evidenced by IκB kinase-α (IKKα) phosphorylation, processing of p100 to p52 and p52/RelB nuclear localization. Remarkably, we found that RelB and p100/p52 were highly expressed in 20-50% of the lobular structures in histologically normal breast tissue obtained from human BRCA1 mutation carriers. After DNA damage, ATM directs the nuclear export of NEMO (NF-κB essential modifier) that in turn activates the alternative NF-κB pathway. We found high levels of phospho-ATM in breast tissue from human BRCA1-mutation carriers and in progenitor cells from BRCA1-knockout mouse mammary glands. Moreover, co-immunoprecipitation studies showed increased ATM/NEMO-containing complexes in BRCA1-deficient cells. Progesterone injections into MMTV-cre;BRCA1f/f mice induced an increase in Ki-67 and phospho-H2AX levels, demonstrating a role for progesterone in DNA damage amplification in mouse mammary glands. Mammary epithelial progenitor cells obtained from BRCA1-mutated carriers as well as BRCA1-/- mouse glands can form acini in Matrigel in a progesterone-independent manner. We found that in vivo inhibition of IKKα/β using the IKK inhibitor dimethylaminoparthenolide (DMAPT) completely blocked mammary acini formation in Matrigel, requiring several estrus cycles post-injection to recover. Importantly, knockdown studies showed that p100/p52 was necessary for progenitor cell proliferation in Matrigel. Consistent with the continued dependence on alternative NF-κB activity in tumors derived from BRCA1-deficient progenitor cells, human breast cancer xenografts derived from BRCA1-mutation carriers infected with lenti-shp100/p52 showed a significant growth inhibition. Overall, these results suggest an exciting new approach for the prevention of breast cancer in patients wherein intermittent or cyclic therapy using DMAPT (generic name LC-1) has the potential to mitigate breast cancer risk in BRCA1 mutation carriers through acute reduction of aberrant progenitor activity. As such, NF-κB-directed chemopreventive therapies may provide promising alternatives to prophylactic mastectomy in this high risk patient population. Citation Format: Andrea Sau, Rosanna Lau, Emma Nolan, Peter A Crooks, Jane E Visvader, Christine MA Pratt. Inhibition of alternative NF-κB activity prevents the expansion of genetically unstable progenitor cells in BRCA1-deficient mammary glands [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-11-04.
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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) | 0.000 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 0.001 |
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".