The new oncogenic factor C11ORF67/AAMDC links RAB/PIK3/MTOR signaling with metabolic reprograming in a subtype of aggressive hormone receptor positive breast cancer

Golden E1,2, Sgro A1,2, Woodward E1,2, Rashwan R1,2, Cuyas E1,3,4, Duffy C1,2, Curtis C5, Jain M6, Redfern A1,2 and Blancafort P1,2

  1. The Harry Perkins Institute of Medical Research, Nedlands, Western Australia, Australia.
  2. The University of Western Australia, Perth, Western Australia, Australia.
  3. Girona Biomedical Research Institute, Girona, Catalonia, Spain.
  4. Catalan Institute of Oncology, Girona, Catalonia, Spain.
  5. Stanford Cancer Institute, Stanford, CA, USA.
  6. University of California San Diego, CA USA.

Recent genomic analysis of breast cancer tumors has identified subtypes of cancers with distinct genetic and molecular profiles which drive variable responses to treatments. Of these subtypes, the intercluster 2 showed one of the poorest prognosis for patient survival, along with amplification of a region of chromosome 11 containing several oncogenic genes. Within this region, C11orf67 was also significantly amplified, although little is known about its function or its role in oncogenesis. We found that expression of C11orf67 is correlated with increased expression of folate cycle enzymes (particularly MTHFD1L), activation of the PI3K signaling pathway, and expression of the transcription factors ATF-4 and c-MYC. C11orf67 also increases susceptibility of cells to the mTOR inhibitors dactolisib and everolimus suggesting that C11orf67 promotes a reliance of the cell on 1C-metabolism for survival. C11orf67 interacts with the Rab GTPase, RABGAP1L. Rabs tightly control vesicle trafficking in the cell and several have been implicated in the regulation of mTORC1activity. These results suggest that C11orf67 supports proliferation and survival of tumour cells through upregulation of the PI3K signaling pathway by targeted vesicular trafficking, resulting in increased ATF-4 and c-MYC-mediated expression of 1C- metabolic enzymes leading to increased amino acid and nucleotide synthesis to support cell growth and proliferation. This study provides a rationale for targeted treatment of these intclus2 cancers through inhibition of PI3K signaling enzymes, folate cycle enzymes and C11orf67 activity through disruption of the interaction with RABGAP1L.