Endocrine Abstracts (2019) 65 P130 | DOI: 10.1530/endoabs.65.P130

Nuclear receptor profiling predicts chemical disruptors as risk factors for developing breast cancer

Freya Leif1, Pauline Pfänder2, Syed Murtuza Baker3, Ian Donaldson3, Kathryn McGinnis1, Fiona Leslie1, James Thorne1, Graham Cook1, Christopher Twelves4, Valerie Speirs5 & Laura Matthews1

1University of Leeds, Leeds, UK; 2German Cancer Research Center, Heidelberg, Germany; 3University of Manchester, Manchester, UK; 4University of Leeds, Leeds, UK; 5University of Aberdeen, Aberdeen, UK

Triple negative breast cancer (TNBC) represents 10–20% of all breast cancers diagnosed, affects young people and is highly aggressive. These tumours lack expression of the receptors that bind estrogen and progesterone and stratify patients for hormonal therapy. The only current therapeutic option for TNBC is chemotherapy which has limited efficacy, and therefore novel therapies are desperately needed. The receptors for estrogen and progesterone belong to the nuclear receptor (NR) superfamily of ligand activated transcription factors. This family comprises 48 receptors which respond to metabolic, reproductive and immune cues. The entire gene set controlled by an individual NR is very specific, but we now realise that groups of NRs control overlapping gene sets, suggesting functional redundancy. NRs therefore work together to regulate key physiological processes, enabling fine tuning and subtle control of essential metabolic, reproductive and immune functions. This suggests that in estrogen receptor (ER) and progesterone receptor (PR) negative breast cancers that other NRs might be important in disease development/progression – and therefore represent tractable therapeutic targets. We have profiled the entire NR superfamily (48 receptors) in 168 breast cancer samples to identify other NRs with altered expression, and in parallel compared NR expression with patient outcome in a larger cohort to link to underlying pathology. We show that a large proportion of the NR superfamily have altered expression in breast cancer, and that 20 of the 48 NRs have altered expression in TNBC compared with normal tissues. The expression of 8 of these were also associated with shorter patient survival times. Using Enrichr software, we identify chemical disruptors – household detergents, antiseptics, industrial pollutants and prescribed medications – predicted to either activate these NRs, or alter their expression. These not only represent risk factors underlying dysregulation of NR function responsible for developing TNBC, but also highlight points for therapeutic intervention.