Poster Presentation 27th Lorne Cancer Conference 2015

OLIGO-ADENYLATE SYNTHETASE-2 (OAS2) INFLUENCES LACTATION, PRIMARY MAMMARY TUMORIGENESIS AND LUNG METASTASIS. (#228)

Samantha R Oakes 1 2 , Anita Ledger 1 , David Gallego-Ortega 1 2 , Claudio M Sergio 1 , Hayley D Cullen 1 , Daniel Roden 1 , Adelaide Young 1 , Wendy Au 1 , Prudence Stanford 1 , Simon Junankar 1 , Matthew J Naylor 3 , Chris C Goodnow 4 , Moira O'Bryan 5 , Christopher J Ormandy 1 2
  1. Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  2. St. Vincent's Clinical School, UNSW Sydney, Darlinghurst, NSW, Australia
  3. Physiology, School of Medical Sciences, Sydney University, Sydney, NSW, Australia
  4. Australian Phenomics Facility, John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia
  5. Department of Anatomy and Developmental Biology, School of Biological Sciences, Monash University, Clayton, Victoria, Australia

Rationale Most breast cancer drugs target molecules and pathways that exhibit developmental phenotypes in the mammary gland when knocked out or mutated in mice. Thus the identification of new genes essential for mammary gland development may yield new therapeutic targets and strategies for the treatment of breast tumours.

Objective We have screened pedigrees carrying ENU induced mutations for failed lactation, an endpoint that integrates all stages of mammary development.

Methods and Results We identified a mutant mouse line that displayed dominant inheritance of poor lactation, with heterozygous dams having litters that failed to thrive and homozygous dams having litters with complete and early pup mortality. The phenotype was apparent only in the post partum period and was characterised by poor alveolar organisation and luminal cell detachment with greatly increased apoptosis associated with a failure of secretory activation. No other phenotypes were observed at necroscopy in aged animals indicating an effect specific to the mammary epithelium. Linkage analysis and exomic sequencing identified a mutation in the coding region of OAS2. OAS2 detects viral dsRNA and activates RNAseL by the synthesis of 2’-5’ oligoadenylates. OAS2-null animals generated from gene trap ES cells showed normal lactation, but compound heterozygous animals (OAS2mut/OAS2null) demonstrated strong genetic interaction between these alleles. Inducible expression of mutant OAS2 in T47D human breast cancer cell lines resulted in apoptosis accompanied by loss of adhesion, altered expression of adhesion proteins and induction of NFkB signalling. Knockdown of RNaseL reversed these effects. Homozygous OAS2 mutants carrying the PyMT oncogene developed mammary tumours that progressed a more rapidly than those in control mice, but strikingly the mutation protected against pregnancy-induced metastasis to lung.

Conclusions This work defines a previously unknown role of the OAS2-RNAseL pathway in lactation and its interaction with carcinogenesis and metatstasis. Since the OAS2 mutant mouse is otherwise normal this information may be exploited to provide a new therapeutic target for breast cancer offering low toxicity. The OAS/RNAseL pathway is currently under intense investigation as a result of the threat posed by emergent viral infections, and the drugs produced by these programs may have an application in cancer therapy.