The BRCA1 gene product and sporadic breast cancers
Isolated in 1994, the BRCA1 gene encodes a 1863 amino acid protein, the role of which remains undetermined. BRCA1 germ-line mutations, which result in loss of functional full-length protein, are associated with familial breast and ovarian cancer. This would suggest an important tumour suppressor role for the BRCA1 protein. No somatic mutations have been described in BRCA1 in sporadic breast cancer cases. Defective transcription or post transcriptional modification of the BRCA1 protein may however precipitate the same outcome of a loss-of-function protein product facilitating the development of sporadic breast cancer as indeed has already been suggested. Progress in the study of BRCA1 has been impeded by the lack of availability of specific, sensitive antibodies. These problems have led to confusion regarding the sub-cellular localisation and postulated functions of BRCA1. This study has endeavoured to answer three questions. Firstly, are the monoclonal antibodies used specific for the BRCA1 protein? Secondly, by immunohistochemical techniques, what is the sub-cellular localisation of the BRCA1 protein within a cohort of primary sporadic breast cancers? And finally, what is the relationship between BRCA1 expression and pathological, biological and survival parameters within a group of 200 primary sporadic breast cancer cases? Results demonstrate Ab2 to detect a 110 kDa protein consistent with the D11b BRCA1 splice variant. This localised to the cytoplasm in both immunohistochemical and western blot settings. Initial pilot study data suggested Ab2 labelling of sporadic breast cancer cases to be of prognostic significance. This was not supported in an expanded study of 200 cases which confirmed that intensity of immunohistochemical labelling was not an independent prognostic indicator in sporadic breast cancer. Ab1 was confirmed to be non-specific.