HORMAD1 (HORMA Domain Containing 1)

Our findings suggest that downregulating HORMAD1 expression could serve as a strategy for restricting TNBC progression by inducing senescence by the p27 pathway.

Consistent with this mechanism, aberrant HORMAD1 expression causes sensitivity to MPS1, Aurora B or BUB1 inhibitors currently being investigated as cancer treatments. Our data suggests how out-of-context expression of a meiotic gene imparts genomic instability upon tumour cells and also identifies several associated dependencies as mechanism-based therapeutic targets for a large, biomarker-defined, subset of cancers.

Isogenic PDX models of TNBC provide a powerful platform to define molecular mechanisms of acquired carboplatin resistance and uncover actionable therapeutic strategies. Our findings reveal multiple adaptive routes to platinum resistance, including restoration of homologous recombination and activation of alternative DNA repair programs. Synergistic interactions between SG and mTOR inhibition offer a promising avenue for overcoming resistance, supporting further clinical investigation of these combinations in TNBC.

Mechanistically, the rs11204679 G > C and rs33924488 GA > G- variants attenuate HOXA6 and SOX15 binding at a distal enhancer, respectively, suppressing HORMAD1 expression via long-range chromatin interactions. These findings establish HORMAD1 as a critical mediator of tobacco-related DNA repair dysregulation and a potential biomarker for ESCC risk stratification and precision prevention.

Further scrutiny via two-sample MR pinpointed UROD, LMO4, HORMAD1, and ZSWIM5 as promising targets for breast cancer therapy. Our research sheds light on new avenues for the treatment of breast cancer, highlighting the potential of genomic association studies in uncovering viable therapeutic targets.

Simultaneous expression of both genes in breast cells in vitro has a synergistic effect that increases stemness and activates a transcriptional profile also observed in double-positive tumors. Therefore, we reveal a functional cooperation between Cancer/Testis genes in basal breast tumors; these findings have consequences for the understanding, diagnosis, and therapy of the breast tumors with the worst outcomes.

Tumor cells proliferate despite encountering chronic replication stress, placing them on the precipice of catastrophic genomic damage. Our data supports the hypothesis that the aberrant expression of HORMAD1 is engaged to attenuate the accumulation of excessive DNA damage due to chronic replication stress, which may otherwise lead to accumulation of toxic levels of genomic instability.

HORMAD1 plays an important role in gastric cancer progression and could be a promising prognostic biomarker and therapeutic target.

Finally, cell-based assays revealed that this HORMA-closure motif interaction pattern contributes to DNA mismatch repair and is required for HORMAD1-dependent HR repair. Together, our results provide structural and biochemical insights into the common theme and functional plasticity of the HORMA domain-containing protein family, and also reveal a universal regulation mechanism for HORMAD1.

shRNA-mediated depletion of HORMAD1 expression resulted in increased genomic instability, DNA damage, increased sensitivity to etoposide, and decreased expression of DNA damage response/repair genes...Furthermore, we identified a meiotic molecular pathway that regulates HORMAD1 expression by targeting the upstream meiosis transcription factor STRA8. Our results highlight a specific relationship between HORMAD1 and genomic instability in SCCs, suggesting that selectively inhibiting HORMAD1, possibly, through STRA8 signaling, may provide a new paradigm of treatment options for HORMAD1-expressing SCCs.

In a second cohort of 186 TNBC patients treated with AC, HORMAD1 expression was associated with longer metastasis-free survival (MFS). In summary, HORMAD1 overexpression was predictive of an improved response to AC in PDX and is an independent prognostic factor in TNBC patients treated with AC.

We identified key genes (CENPW, HORMAD1, APOD, PIP, and ZNF703) associated with poor OS. Thus, these genes might serve as candidate prognostic markers for TNBC.