Expression of a truncated Brca1 protein delays lactational mammary development in transgenic mice.
To address the hypothesis that certain disease-associated mutants of the breast-ovarian cancer susceptibility gene BRCA1 have biological activity in vivo, we have expressed a truncated Brca1 protein (trBrca1) in cell-lines and in the mammary gland of transgenic mice. Immunofluorescent analysis of transfected cell-lines indicates that trBRCA1 is a stable protein and that it is localized in the cell cytoplasm. Functional analysis of these cell-lines indicates that expression of trBRCA1 confers an increased radiosensitivity phenotype on mammary epithelial cells, consistent with abrogation of the BRCA1 pathway. MMTV-trBrca1 transgenic mice from two independent lines displayed a delay in lactational mammary gland development, as demonstrated by altered histological profiles of lobuloalveolar structures. Cellular and molecular analyses indicate that this phenotype results from a defect in differentiation, rather than altered rates of proliferation or apoptosis. The results presented in this paper are consistent with trBrca1 possessing dominant-negative activity and playing an important role in regulating normal mammary development. They may also have implications for germline carriers of BRCA1 mutations.
Brown
Melissa A
MA
Department of Medical and Molecular Genetics, King's College London, Guy's Hospital, UK. melissa.brown@mailbox.uq.edu.au
Nicolai
Hans
H
Howe
Kathy
K
Katagiri
Toyomasa
T
Lalani
El-Nasir
el-N
Simpson
Kaylene J
KJ
Manning
Nathan W
NW
Deans
Andrew
A
Chen
Phil
P
Khanna
Kum Kum
KK
Wati
Mas Rina
MR
Griffiths
Beatrice L
BL
Xu
Chun-Fang
CF
Stamp
Gordon W H
GW
Solomon
Ellen
E
D000818:Animals; D019313:BRCA1 Protein / Q000235:genetics* / Q000378:metabolism; D015415:Biomarkers / Q000032:analysis; D015153:Blotting, Western; D017931:DNA Primers / Q000737:chemistry; D004847:Epithelial Cells / Q000378:metabolism* / Q000528:radiation effects; D005260:Female; D005455:Fluorescent Antibody Technique; D017353:Gene Deletion; D015870:Gene Expression; D005822:Genetic Vectors; D020287:In Situ Nick-End Labeling; D007774:Lactation / Q000502:physiology*; D008297:Male; D008321:Mammary Glands, Animal / Q000166:cytology / Q000502:physiology* / Q000528:radiation effects; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D016133:Polymerase Chain Reaction; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000378:metabolism*; D011836:Radiation Tolerance; D014162:Transfection
D019313:BRCA1 Protein; D015415:Biomarkers; D017931:DNA Primers