Flash Talk & Poster Presentation 31st Lorne Cancer Conference 2019

Estrogen receptor (ER) positive luminal progenitors identified as the cancer cell of origin for ER+ breast cancer (#102)

Genevieve V Dall 1 , Serene Yeow 1 , Jessica Vieusseux 1 , Yashar Razavi 2 , Nathan Godde 1 , Mandy Ludford-Menting 1 , Sarah Russell 1 3 , Alan Ashworth 4 , Robin Anderson 1 5 , Gail Risbridger 1 2 , Mark Shackleton 6 7 , Kara L Britt 1 6
  1. Peter MacCallum Cancer Centre, Melbourne
  2. Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, Australia
  3. Centre for Micro-Photonics, , Swinburne University, Hawthorn
  4. UCSF Helen Diller Family , Comprehensive cancer centre, San Francisco, USA
  5. Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria
  6. Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia
  7. Cancer Development and Treatment, Monash University, Alfred Hospital, Melbourne

The incidence of breast cancer (BCa) is rising worldwide and of all the BCa subtypes it is only estrogen receptor (ER) positive cancers that are driving this increase. Changing reproductive trends are accepted to be the cause of an increase in incidence, with women having fewer children than 3 decades ago, and on average bearing them later in life, when the protective effects of childbearing are less significant. Moreover, we are experiencing menarche earlier, menopause later and commonly use exogenous hormonal supplements (Oral contraceptives, HRT), which all increase lifetime estrogen exposure.

We assessed the cell specific changes in the mammary glands of mice at risk of developing ER+ BCa (nulliparous mice, mice exposed to 6wks of estrogen treatment, or pre-neoplastic glands from a mouse model of ER+ BCa) in order to identify initiating events leading to the development of ER+ BCa.  We compared these changes to those in mice protected against BCa (ovariectomised, treated with anti-estrogens for 6wks or mice that were multi-parous). 

We found that ER+ luminal progenitors were specifically and significantly reduced (both in number and colony forming ability) following parity. Mice exposed to exogenous estrogen (0.3mg) for just 6 weeks had increased ER+ luminal progenitors and conversely those either ovariectomised or treated with the antiestrogen fulvestrant (ICI 182-780, 5mg) or Tamoxifen (1mg) had decreased ER+ luminal progenitors. Further characterisation of the ER+ luminal progenitors revealed this rare subpopulation to be more sensitive to carcinogen insult, with higher g-H2AX levels measured compared to MaSC following radiation exposure, and a greater loss in colony-forming ability compared to their ER neg counterparts in response to two types of carcinogens. RNAseq experiments are underway to confirm that the gene expression profile of ER+ luminal progenitors are over represented in ER+ BCa.

Our findings implicate ER+ as the cancer cell of origin for ER+ BCa and the ideal target for novel breast cancer therapies and preventatives with less side effects than Tamoxifen.