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2024

Dev Cell. 2024 May 20:S1534-5807(24)00298-3. doi: 10.1016/j.devcel.2024.04.022.

Ehf controls mammary alveolar lineage differentiation and is a putative suppressor of breast tumorigenesis

Rebecca Nightingale, Camilla M Reehorst, Natalia Vukelic, Nikolaos Papadopoulos, Yang Liao, Shalini Guleria, Caroline Bell, François Vaillant, Sudip Paul, Ian Y Luk, Amardeep S Dhillon, Laura J Jenkins, Riley J Morrow, Felicity C Jackling, Ashwini L Chand, David Chisanga, Yunshun Chen, David S Williams, Robin L Anderson, Sarah Ellis, Peter J Meikle, Wei Shi, Jane E Visvader, Bhupinder Pal, John M Mariadason

Department of Medical Biology, University of Melbourne, Parkville, VIC 3052, Australia. Metabolomics Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia. Baker Department of Cardiovascular Research Translation and Implementation, La Trobe University, Bundoora, VIC 3086, Australia. The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Deakin University, Geelong, VIC 3220, Australia. Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute, Parkville, VIC 3052, Australia. Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia. Department of Pathology, Austin Health, Heidelberg, VIC 3084, Australia. The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC 3052, Australia. Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia; School of Cancer Medicine, La Trobe University, Bundoora, VIC 3086, Australia.

Service type: Knockout mice

Abstract

The transcription factor EHF is highly expressed in the lactating mammary gland, but its role in mammary development and tumorigenesis is not fully understood. Utilizing a mouse model of Ehf deletion, herein, we demonstrate that loss of Ehf impairs mammary lobuloalveolar differentiation at late pregnancy, indicated by significantly reduced levels of milk genes and milk lipids, fewer differentiated alveolar cells, and an accumulation of alveolar progenitor cells. Further, deletion of Ehf increased proliferative capacity and attenuated prolactin-induced alveolar differentiation in mammary organoids. Ehf deletion also increased tumor incidence in the MMTV-PyMT mammary tumor model and increased the proliferative capacity of mammary tumor organoids, while low EHF expression was associated with higher tumor grade and poorer outcome in luminal A and basal human breast cancers. Collectively, these findings establish EHF as a non-redundant regulator of mammary alveolar differentiation and a putative suppressor of mammary tumorigenesis.

Keywords: EHF; alveologenesis; breast cancer; breast tumorigenesis; mammary development; mammary gland; mouse; organoid; post-natal mammary development; transcription factor.

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