Abstract P2-06-01: Characterisation of C11orf67, an oncogenic driver in a new subtype of aggressive endocrine receptor positive breast cancer
Authors: A Redfern, R Rashwan, A Sorolla, M Ratajska, I Kardas, A Kuzniacka, J Parry, C Curtis, A Woo, A Sgro, W Biernat
Journal: Cancer Research (2016)

Abstract The recent integration of both genomic and transcriptomic datasets have added a further dimension to the landscape of breast cancer (BrCa) subtyping, defining novel functional subgroups with distinctive oncogenic drivers that carry important implications for therapy. This integrative clustering has unveiled a novel subtype of hormone receptor positive (HR+) BrCa associated with high proliferation and very poor survival characterised by copy number amplification and overexpression of a cluster of candidate oncogenic drivers at the 11q13.5-14 locus (1). At the heart of this amplicon we have demonstrated the selective overexpression of C11orf67/AAMDC (Adipogenesis associated Mth938 domain containing) which encodes a hypothetical protein of 122 aa with unknown function. In a pilot tissue microarray of 75 BrCa cases C11orf67 amplification and expression were significantly correlated with hormone receptor positivity. These positive cases also demonstrated high risk features with 75% demonstrating lymph node involvement. In functional elucidation studies knockdown of C11orf67 in the highly expressing T47D cell line lead to decreased cell proliferation, cell migration, anchorage independent cell growth and induction of senescence. T47D xenografts with stable shRNA-induced C11orf67 knockdowns introduced into BALB/c mice showed significantly lower tumour volumes relative to T47D with empty vector. A genome wide analysis of these T47D-C11orf67 shRNA cells compared to T47D-empty vector cells using the Illumina HumanHT-12 platform demonstrated 40 differentially expressed genes. Network analysis revealed a proliferation node, enriched in cell cycle proteins, and a metabolic node comprising several biosynthetic enzymes such as MTHFD1L involved in one-carbon folate metabolism. Supporting this link and pointing to potential utility in chemotherapy selection, induction of ectopic C11orf67 expression in MCF7 cells increased sensitivity to fluorouracil and methotrexate but not to paclitaxel. Investigating potential novel binding partners and effectors, in yeast two hybrid screening C11orf67 was a found to associate strongly with RABGAP1L, a protein involved in controlling GTPase signalling, protein trafficking, and autophagy. Exploring the molecular cues that control C11orf67 expression, our data suggest the locus is regulated by transcription factors associated with high proliferation and metabolic control, notably Myc and NFkB, as well as HRs. E2 lead to a significant down-regulation of C11orf67 in T47D cells, which was reversed by the antiestrogen drug tamoxifen, whereas PG significantly increased C11orf67 levels. In keeping with this MCF7 cells ectopically expressing C11orf67 were resistant to the anti-proliferative effects of tamoxifen compared to the parent cell line. These observations endorse C11orf67 as a novel oncogenic driver with exciting therapeutic potential, which could serve to distinguish the HR+ tumours at high risk of relapse and guide both the selection of current chemotherapeutical and endocrine treatments as well as the design of future precision therapeutics, notably anti-folate/one carbon drugs and novel endocrine agents. References 1. Curtis et al. Nature. 2012 Jun 21;486 (7403):346-52. Citation Format: Redfern A, Rashwan R, Sorolla A, Ratajska M, Kardas I, Kuzniacka A, Parry J, Curtis C, Woo A, Sgro A, Biernat W. Characterisation of C11orf67, an oncogenic driver in a new subtype of aggressive endocrine receptor positive breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-06-01.