BRCA1 is a key regulator of breast differentiation through activation of Notch signalling with implications for anti-endocrine treatment of breast cancers

• Published in: Nucleic acids research Vol. 41; no. 18; pp. 8601 - 8614
• Main Authors: Buckley, Niamh E, Nic An tSaoir, Caoimhe B, Blayney, Jaine K, Oram, Lisa C, Crawford, Nyree T, D'Costa, Zenobia C, Quinn, Jennifer E, Kennedy, Richard D, Harkin, D Paul, Mullan, Paul B
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01-10-2013
• Subjects: Animals; BRCA1 Protein - physiology; Breast - cytology; Breast - metabolism; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Breast Neoplasms - therapy; Calcium-Binding Proteins - genetics; Cell Differentiation; Cell Line; Embryonic Stem Cells - metabolism; Estrogen Antagonists - pharmacology; Female; Humans; Intercellular Signaling Peptides and Proteins - genetics; Jagged-1 Protein; MCF-7 Cells; Membrane Proteins - genetics; Mice; Molecular Biology; Receptor, Notch1 - genetics; Receptors, Notch - biosynthesis; Receptors, Notch - genetics; Receptors, Notch - metabolism; Serrate-Jagged Proteins; Signal Transduction - genetics; Tamoxifen - pharmacology; Transcription Factors - physiology; Transcription, Genetic; Tumor Suppressor Proteins - physiology; Up-Regulation
• ISSN: 0305-1048; 1362-4962
• DOI: 10.1093/nar/gkt626

Here, we show for the first time, that the familial breast/ovarian cancer susceptibility gene BRCA1 activates the Notch pathway in breast cells by transcriptional upregulation of Notch ligands and receptors in both normal and cancer cells. We demonstrate through chromatin immunoprecipitation assays that BRCA1 is localized to a conserved intronic enhancer region within the Notch ligand Jagged-1 (JAG1) gene, an event requiring ΔNp63. We propose that this BRCA1/ΔNp63-mediated induction of JAG1 may be important the regulation of breast stem/precursor cells, as knockdown of all three proteins resulted in increased tumoursphere growth and increased activity of stem cell markers such as Aldehyde Dehydrogenase 1 (ALDH1). Knockdown of Notch1 and JAG1 phenocopied BRCA1 knockdown resulting in the loss of Estrogen Receptor-α (ER-α) expression and other luminal markers. A Notch mimetic peptide could activate an ER-α promoter reporter in a BRCA1-dependent manner, whereas Notch inhibition using a γ-secretase inhibitor reversed this process. We demonstrate that inhibition of Notch signalling resulted in decreased sensitivity to the anti-estrogen drug Tamoxifen but increased expression of markers associated with basal-like breast cancer. Together, these findings suggest that BRCA1 transcriptional upregulation of Notch signalling is a key event in the normal differentiation process in breast tissue.