Mammary Lineage-dependent Homologous Recombination Repair and PARP Inhibitor Vulnerability
Bibliographic record
Abstract
Deleterious germline mutations in the key homologous recombination (HR) repair genes, such as BRCA1/2, strikingly increase the lifetime risk for breast cancer, underscoring the importance of faithful double-strand break (DSB) repair in maintaining the genome integrity of mammary epithelial cells. It has long been assumed that all normal cells have the same capacity to engage high-fidelity HR and error-prone non-homologous end joining (NHEJ) to repair DSBs, and that the choice between these two DSB repair pathways are determined by the cell cycle. Here, we show that the two major mammary epithelial lineages, basal and luminal, are not equally equipped to resolve DSBs. Global proteomic analyses of primary mouse mammary epithelial subpopulations and enumeration of their DSB repair activities have revealed that HR is predominantly restricted to the luminal lineage, while NHEJ operates in all mammary epithelial cells. This intrinsic differential HR repair translates into a divergent sensitivity to poly(ADP-ribose) polymerase inhibitors (PARPi), selectively reducing basal clonogenicity while sparing luminal progenitors, in both the mouse and human, irrespective of BRCA mutation status. Furthermore, we generated proteome-defined lineage-specific signatures, referred to as basal or luminal progenitor identification (ID), that correlate to the PAM50 breast cancer subtypes and predict the PARPi response of triple-negative human breast cancer xenografts. Thus, mammary epithelial cell types underpin a new strategy for identifying PARPi responders. We further sought to potentiate the efficacy of PARPi by concurrently blocking progesterone receptor given its pro-tumorigenic role in the BRCA1/2-mutated carriers. This novel PARPi combination with a selective progesterone receptor modulator, ulipristal acetate (UA), abrogated clonogenicity of both lineages from primary, high-risk breast tissue specimens. Altogether, we demonstrate that mammary cell lineage is an unprecedented determinant of DSB repair pathway choice, and understanding cell lineage-restricted vulnerabilities can be leveraged to enhance intervention strategies for improved therapeutic outcomes in high-risk women.
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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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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 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".