The BRCA1 gene was previously found to inhibit the transcriptional activity of the estrogen receptor [ER-a] in human breast and prostate cancer cell lines. In this study, we found that breast cancer-associated mutations of BRCA1 abolish or reduce its ability to inhibit ER-a activity and that domains within the amino-and carboxyltermini of the BRCA1 protein are required for the inhibition. BRCA1 inhibition of ER-a activity was demonstrated under conditions in which a BRCA1 transgene was transiently or stably over-expressed in cell lines with endogenous wild-type BRCA1 and in a breast cancer cell line that lacks endogenous functional BRCA1 (HCC1937). In addition, BRCA1 blocked the expression of two endogenous estrogen-regulated gene products in human breast cancer cells: pS2 and cathepsin D. The BRCA1 protein was found to associate with ER-a in vivo and to bind to ER-a in vitro, by an estrogen-independent interaction that mapped to the amino-terminal region of BRCA1 (ca. amino acid 1-300) and the conserved carboxyl-terminal activation function [AF-2] domain of ER-a. Furthermore, several truncated BRCA1 proteins containing the amino-terminal ER-a binding region blocked the ability of the full-length BRCA1 protein to inhibit ER-a activity. Our ®ndings suggest that the aminoterminus of BRCA1 interacts with ER-a, while the carboxyl-terminus of BRCA1 may function as a transcriptional repression domain. Oncogene (2001) 20, 77 ± 87.

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Purpose: To determine if mosaic tuberous sclerosis complex (TSC) can be stratified into subtypes that correspond with prognosis and extent of disease. Methods: Next-generation sequencing of skin tumor and other samples was used to identify patients with mosaic pathogenic variants in TSC1 or TSC2 . Extent of disease, onset age, and family history of TSC were determined through retrospective analysis of patient records. Results: The median number of disease findings and age at penetrance differed between mosaic patients with asymmetrically distributed facial angiofibromas (4 findings, 24y, n=7), mosaic patients with bilaterally symmetric facial angiofibromas (8 findings, 10y, n=12), and germline TSC patients (10 findings, 4y, n=29). Cutaneous and internal organ involvement positively correlated in mosaic (R=0.62, p=0.005), but not germline (R=−0.24, p=0.24) TSC. Variant allele fraction (VAF) in the blood (range: 0-19%) positively correlated with the number of major features (R=0.55, p=0.028). Five had a TSC2 variant identified in the skin that was below detection in the blood. One of 12 children from a mosaic parent had TSC. Conclusion: The phenotype of mosaic TSC ranged from mild to indistinguishable from germline disease. Patients with mosaicism and asymmetric facial angiofibromas exhibited fewer findings, later onset, and lower VAF in the blood.