Abstract
Adipogenesis associated Mth938 domain containing (AAMDC) represents an uncharacterized oncogene amplified in aggressive estrogen receptor-positive breast cancers. We uncover that AAMDC regulates the expression of several metabolic enzymes involved in the one-carbon folate and methionine cycles, and lipid metabolism. 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. 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. Ectopic AAMDC expression is sufficient to activate AKT signaling, resulting in estrogen-independent tumor growth. Thus, AAMDC-overexpressing tumors may be sensitive to PI3K-mTORC1 blockers in combination with anti-estrogens. Lastly, we provide evidence that AAMDC can interact with the RabGTPase-activating protein RabGAP1L, and that AAMDC, RabGAP1L, and Rab7a colocalize in endolysosomes. The discovery of the RabGAP1L-AAMDC assembly platform provides insights for the design of selective blockers to target malignancies having the AAMDC amplification.
Highlights
Adipogenesis associated Mth[938] domain containing (AAMDC) represents an uncharacterized oncogene amplified in aggressive estrogen receptor-positive breast cancers
We found a stronger trend for differentially expressed genes (DEGs) in dactolisib-treated cells to up- or downregulate in the same direction as the DEGs in the associated Mth938 domain containing (AAMDC) KD, suggesting similar downstream targets, compared to the other inhibitors that were tested (Fig. 5b).Various metabolic processes were enriched in the gene ontology (GO) term analysis for genes commonly downregulated between the KD and at least three of the drug treatments (Fig. 5c, Supplementary Fig. 4, Supplementary Data 4)
Discussion we have unveiled the function of AAMDC, an oncogene selectively amplified in ~25% of luminal B breast cancers (BCs), which often exhibit anti-E2 resistance and very poor prognoses[24,25]
Summary
Adipogenesis associated Mth[938] domain containing (AAMDC) represents an uncharacterized oncogene amplified in aggressive estrogen receptor-positive breast cancers. 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] Current diagnostic tests, such as Oncotype Dx, are limited to the determination of whether the addition of cytotoxic chemotherapy can provide a therapeutic benefit, rather than identifying rational drug targets to directly inhibit oncogenic drivers[4]. The hallmark of IntClust[2] tumors is focal amplification of a region of chromosome (chr 11) (11q13.5–14.1) defining a cis-acting oncogenic cluster[5] This subtype harbors genomic and transcriptional alterations in cell cycle-related genes, including the MYC targets CCND1 and CCNE1, and displays aggressive behavior including a high level of proliferation and endocrine therapy resistance[5]. We propose that the identification of AAMDC-overexpressing tumors could facilitate the identification of patients with a poor prognosis and the development of selective therapeutic interventions against this aggressive subtype of ER+ disease
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