Flash Talk + Poster Presentation 38th Lorne Cancer Conference 2026

Kap1 maintains the hormone response of the mammary gland (#106)

Michael Milevskiy 1 2 3 , Hao-Chun Chang 1 2 , Felicia Ong 1 , Felicity Jackling 1 , Somi Kordafshari 1 2 , Amy Tsai 1 , François Vaillant 1 2 , Elliot Surgenor 1 , Yunshun Chen 1 2 4 , Geoffrey Lindeman 1 2 5 6 , Jane Visvader 1 2
  1. Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  2. Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia
  3. School of Pharmacy & Pharmaceutical Sciences, Cardiff University, Cardiff, Wales, United Kingdom
  4. School of Mathematics and Statistics, The University of Melbourne, Parkville, Victoria, Australia
  5. Parkville Familial Cancer Centre and Department of Medical Oncology, The Royal Melbourne Hospital, Parkville, Victoria, Australia
  6. Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, Australia

The ovarian hormones, oestrogen and progesterone, are major drivers of breast tumourigenesis. Both hormones are essential for mammary gland development: oestrogen is the key driver of morphogenesis during puberty while progesterone drives tertiary branching in the adult and in pregnancy, helping to coordinate development of alveolar cells. Oestrogen and progesterone bind to their cognate hormone receptors (HR), ER⍺ and PR respectively which then bind to DNA, regulating gene expression. KAP1/TRIM28/TIF1β has recently been identified as a cofactor for HR action in the uterus. KAP1 loss results in reduced activity of ER⍺ and PR binding sites in uterine cells. These data suggest that KAP1 is an essential mediatory of HR action. Generating a mouse model of mammary specific Kap1 loss we have found that mammary gland development is delayed during puberty and in pregnancy, alveologenesis was profoundly affected, leading to impaired lactation. Kap1 binding sites overlap with ER⍺ and PR sites in HR+ epithelial cells within the mammary gland. Interestingly, loss of Kap1 increases the binding of ER⍺, PR and their cofactors across the genome, increasing the expression of genes not normally associated with HR+ breast cells including Csf1r, Egfr, Il34 and Rank. This rewiring of HR genomic action appears to lead to the uncontrolled proliferation of HR+ cells during pregnancy. In human breast tumours, KAP1 is most highly expressed in ER+/PR+ tumours compared to the more aggressive ER+/PR– tumours where KAP1 expression is lower. These findings suggest that KAP1 protects the mammary gland from spurious activity of HR receptors during development and may influence tumour behaviour in patients with HR+ breast cancer.