Androgen pathway dysregulation in BRCA1-mutated breast tumors.
BACKGROUND
Using array analysis for screening RNA from BRCA1-mutated and sporadic breast tumors, we observed that AIGF/FGF-8 expression was lost in BRCA1-mutated breast tumors. Since this growth factor is induced by androgens, we studied the androgen receptor (AR) expression in BRCA-mutated tumors and in matched sporadic breast tumors.


METHODS
Paraffin embedded breast tumors of carriers of a BRCA1 mutation (n=41, median age of patients at time of surgery was 41 years [range 28-59 years]) or a BRCA2 mutation (n=14, median age 41 years [range 31-85 years]) were analyzed for the presence of ER-alpha, PR, P53 and AR using standard immunohistochemical techniques. All statistical tests used, Pearson chi2 and Fisher exact, were two-sided.


RESULTS
The AR was only present in 12% of BRCA1-mutated tumors, with mutations located at the C-terminal half of the BRCA1-gene. The AR expression was significantly more prevalent, however, in a series of 61 sporadic breast tumors (80%) and in BRCA2-mutated tumors (50%). In contrast to an increased percentage of p53 positive cells, in 66% of the BRCA1-mutated tumors, the ER-alpha expression was observed only in 25% and the PR in 13% of these specimens. The three steroid hormone receptors were expressed in about half of the BRCA2-mutated specimens studied.


CONCLUSIONS
Our data add to the emerging evidence that the biological phenotype of BRCA1-associated tumors may be different from BRCA2 and non-hereditary cases. The loss of the AR expression, as shown by immunohistochemistry, together with the observed loss of other steroid hormone receptors in BRCA1-mutated tumors may lead to a hormone-independent growth or to anti-hormone resistant growth of these tumors.
Berns
Els M J J
EM
Department of Medical Oncology, Josephine Nefkens Institute, Erasmus MC, Rotterdam, The Netherlands. p.m.j.j.berns@erasmusmc.nl
Dirkzwager-Kiel
Maaike J M
MJ
Kuenen-Boumeester
Vibeke
V
Timmermans
Mieke
M
Verhoog
Leon C
LC
van den Ouweland
Ans M W
AM
Meijer-Heijboer
Hanne
H
Klijn
Jan G M
JG
van der Kwast
Theo H
TH
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism*; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D006801:Humans; D007150:Immunohistochemistry; D016555:Matched-Pair Analysis; D008875:Middle Aged; D009154:Mutation; D011944:Receptors, Androgen / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D011987:Receptors, Steroid / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D011944:Receptors, Androgen; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D011987:Receptors, Steroid; D016159:Tumor Suppressor Protein p53