To date, there are no clinical biomarkers to stratify the fraction of HR + tumors with a high probability of relapse from the bulk of malignancies that respond to traditional anti-hormonal approaches 3.

While luminal A tumors generally respond well to anti-hormonal therapies, luminal B tumors often lose HR-driven transcriptional programs and have higher rates of mortality 3. The discovery of the RabGAP1L-AAMDC assembly platform provides insights for the design of selective blockers to target malignancies having the AAMDC amplification.Īnalysis of transcriptomic data has traditionally stratified breast cancers (BCs) into six subtypes: hormone receptor-positive (HR +) luminal A and luminal B, HER2-enriched (HER2 +), basal-like, claudin-low, and normal-like 1, 2.

Lastly, we provide evidence that AAMDC can interact with the RabGTPase-activating protein RabGAP1L, and that AAMDC, RabGAP1L, and Rab7a colocalize in endolysosomes. Thus, AAMDC-overexpressing tumors may be sensitive to PI3K-mTORC1 blockers in combination with anti-estrogens. Ectopic AAMDC expression is sufficient to activate AKT signaling, resulting in estrogen-independent tumor growth. High AAMDC expression is associated with sensitization to dactolisib and everolimus, and these PI3K-mTOR inhibitors exhibit synergistic interactions with anti-estrogens in IntClust2 models. We show that AAMDC controls PI3K-AKT-mTOR signaling, regulating the translation of ATF4 and MYC and modulating the transcriptional activity of AAMDC-dependent promoters. We uncover that AAMDC regulates the expression of several metabolic enzymes involved in the one-carbon folate and methionine cycles, and lipid metabolism. Adipogenesis associated Mth938 domain containing (AAMDC) represents an uncharacterized oncogene amplified in aggressive estrogen receptor-positive breast cancers.

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