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Preprint WatchModerateSeptember 17th, 2026

ERBB2 establishes the timing of progesterone priming required for uterine receptivity

Li, B.; Zhang, C.; Dewar, A.; Liu, X.; Deng, W.; Qi, H.; Dey, S. K.; Sun, X.

ERBB2 sets the timing of stromal progesterone responsiveness by controlling the threshold for progesterone receptor induction; uterine Erbb2 deletion in mice defers implantation and impairs decidualization, and ERBB2 is downregulated in endometrial stroma from women with recurrent spontaneous abortion.

Moderate contradiction

2 prior failures

Two documented clinical failures match this mechanism, or a single Phase 3 failure is on record.

The claim here is on-target rather than anti-tumour: ERBB2 controls the timing of stromal progesterone priming, and losing it defers implantation in mice while tracking with recurrent spontaneous abortion in human endometrium. The two ERBB2 entries in the Claidex graph are oncology programs stopped for other reasons, an antibody drug conjugate discontinued as a strategic reprioritization (xmt-2056-erbb2-her2-sting-agonist-adc-phase1-strategic-discontinuation) and a tyrosine kinase inhibitor whose exon 20 hypothesis did not transfer to patients (poziotinib-erbb2-her2-exon20-nsclc-zenith20-phase2-translational-mismatch). Neither failure speaks to reproductive biology, so this is a breadth flag rather than a contradiction. It matters because it names a physiological ERBB2 function in a tissue that HER2-directed agents reach, which belongs in the risk assessment for sustained HER2 blockade in patients of reproductive age.

Abstract excerpt

Progesterone is essential for establishing uterine receptivity and sustaining early pregnancy. However, how the uterus acquires the competence to respond to progesterone at the appropriate time remains poorly understood. Here we show that ERBB2 governs the timing of progesterone responsiveness required for uterine receptivity. In endometrial samples from women with recurrent spontaneous abortion (RSA), ERBB2 is downregulated specifically in the stromal compartment, accompanied by a parallel reduction in stromal progesterone receptor (PGR). Uterine deletion of Erbb2 in mice blunts the rise of stromal PGR at the onset of the receptive window, deferring implantation and impairing decidualization despite normal circulating progesterone and estrogen. Epithelial deletion has no such effect, placing the requirement in the stroma. High-dose progesterone fails to rescue the phenotype; advancing progesterone priming by 24 hours restores stromal PGR, HAND2, Bmp2, and on-time implantation. Collectively, the present study provides evidence that ERBB2 directs the temporal window of stromal progesterone priming by setting the threshold for PGR induction, thereby synchronizing the maternal-fetal interface and safeguarding pregnancy.

Matching Claidex post-mortems

2 of 2 indexed

This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.