Poster Presentation 35th Lorne Cancer Conference 2023

Expression of APOBEC genes in breast luminal progenitor cells (#246)

Conor F McGuinness 1 2 , Mik A Black 1 , Anita K Dunbier 1
  1. Centre for Translational Cancer Research, Department of Biochemistry, University of Otago, Dunedin, Otago, New Zealand
  2. Peter MacCallum Cancer Centre, Melbourne, VIC, Australia

   APOBEC3A and APOBEC3B have been implicated as drivers of mutagenesis in a range of solid tumour types, including breast cancer. A genetic polymorphism that deletes the entire coding region of the APOBEC3B gene has been associated with an increased risk of breast cancer and higher rates of APOBEC hypermutation in breast tumours1,2. The proposed mechanism by which mutagenesis occurs in carriers does not account for the exclusivity of this association in oestrogen receptor positive (ER+) breast cancer. We hypothesised that the antisense lncRNA APOBEC3B-AS1 could play a role in the regulation of APOBEC3A/B and thus mediate APOBEC hypermutation in carriers of the APOBEC deletion polymorphism.

   scRNAseq data derived from developing blastocysts3,4 indicated that the current annotation of APOBEC3B-AS1 is truncated at the 3’ end. Here we denote the non-truncated transcript as ALBEX1. UMAP clustering revealed a cluster of cells expressing ALBEX1 concurrently with APOBEC3B, as well as pluripotency genes such as NANOG and NODAL. In a separate dataset derived from healthy breast tissue5, a cluster of cells expressing ALBEX1 and APOBEC3B was identified. This cluster was enriched with genes indicative of ER+ luminal progenitor cells (LPs) such as KRT8/18 and ELF5.

   Publically available ChIP-seq data indicates that the promoters of ALBEX1 and APOBEC3B may be under the influence of an enhancer element that binds ER and CTCF/cohesin to drive concurrent expression of these genes. This CTCF site is lost in carriers of the APOBEC deletion polymorphism, and may lead to increased expression of promutagenic, catalytically efficient APOBEC3A in LPs and subsequent genomic hypermutation.

   Empirical approaches are now required to determine the role of ALBEX1 in the regulation of APOBEC3A/B. Additionally, our analyses suggest that the APOBEC mutation signature may be found in LPs and mature breast epithelial cells in APOBEC deletion polymorphism carriers. Validation of this hypothesis, in parallel with the results presented above, would contribute to a growing body of evidence suggesting that LPs are the cell-of-origin in ER+ breast cancer. Targeting this subset could thus lead to improved breast cancer prevention strategies.

  1. Xuan, D. et al. APOBEC3 deletion polymorphism is associated with breast cancer risk among women of European ancestry. Carcinogenesis 34, 2240–2243 (2013)
  2. Nik-Zainal, S. et al. Association of a germline copy number polymorphism of APOBEC3A and APOBEC3B with burden of putative APOBEC-dependent mutations in breast cancer. Nat. Genet. 46, 487–491 (2014).
  3. Yan, L. et al. Single-cell RNA-Seq profiling of human preimplantation embryos and embryonic stem cells. Nat. Struct. Mol. Biol. 20, 1131–1139 (2013).
  4. Petropoulos, S. et al. Single-Cell RNA-Seq Reveals Lineage and X Chromosome Dynamics in Human Preimplantation Embryos. Cell 165, 1012–1026 (2016).
  5. Bhat-Nakshatri, P. et al. A single-cell atlas of the healthy breast tissues reveals clinically relevant clusters of breast epithelial cells. Cell Rep. Med. 2, 100219 (2021).