posters International Association for Breast Cancer Research 2014

Jersey regulates mammary development and plays a key role in human breast carcinogenesis (#81)

Samantha 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. The School of Biological Sciences, Monash University, Clayton, VIC, Australia

Rationale The identification of genes essential for the survival of mammary epithelium may yield novel therapeutic targets for the treatment of a wide range of breast tumours.

Objective We have used ENU mutagenesis to look for phenotypes of reduced mammary epithelial cell viability and failed lactation.

Methods and Results We have identified a dominant mutant mouse line (Jersey) that displayed reduced mammary epithelial viability. We observed premature involution in Jer/Jer homozygous mutants characterised by poor alveolar organisation and luminal cell detachment, which resulted in complete failure of lactation and pup mortality by 4 days post-partum (dpp). Epithelial cells in Jer/Jer mammary glands displayed reduced proliferation at mid-pregnancy and increased apoptosis at 2 days post partum. Mammary glands produced by transplanting Jer/Jer mammary epithelium into cleared WT mammary fat pads showed a similar defect indicating that the mutation acted in a mammary cell autonomous fashion. No other defects were observed in other organs and suggested the Jersey defect was specific to the mammary epithelium. Enforced expression of the Jersey mutation in T47D human breast cancer cell lines resulted in loss of adhesion, apoptosis and altered expression of adhesion proteins. Knockdown of a downstream target of Jersey reversed these effects and suggested that the mutation resulted in constitutive activation of the Jersey pathway. Homozygous Jersey mutants carrying the PyMT oncogene developed mammary tumours that progressed more rapidly than those in control mice. Furthermore, high expression of Jersey and its signalling partners was correlated with poor overall survival and metastasis free survival in human breast cancers (Oncomine™ (Compendia Bioscience, Ann Arbor, MI).

Conclusions This work defines a previously unknown role of Jersey in mammary development and carcinogenesis. Since the Jersey mouse is otherwise normal this information may be exploited to provide a new therapeutic target for breast cancer offering low toxicity.