{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T23:21:55Z","timestamp":1791328915333,"version":"4.3.1"},"reference-count":59,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2004,1,8]],"date-time":"2004-01-08T00:00:00Z","timestamp":1073520000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes Chromosomes &amp;amp; Cancer"],"published-print":{"date-parts":[[2004,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The breast cancer susceptibility genes <jats:italic>BRCA1<\/jats:italic> and <jats:italic>BRCA2<\/jats:italic> are responsible for a large proportion of familial breast and ovarian cancer, yet little is known of how disruptions in the functions of the proteins these genes encode increased cancer risk preferentially in hormone\u2010dependent tissue. There is no information on whether a germ\u2010line mutation in <jats:italic>BRCA1<\/jats:italic> or <jats:italic>BRCA2<\/jats:italic> causes disruptions in hormone\u2010signaling pathways in the normal breast. In this study markers of hormone responsiveness were measured in prophylactically removed normal breast tissue (<jats:italic>n<\/jats:italic> = 31) in women bearing a germ\u2010line pathogenic mutation in one of the <jats:italic>BRCA<\/jats:italic> genes. The estrogen receptor (ER) and proteins associated with ER action in hormone\u2010sensitive tissues, namely, PS2 and the progesterone receptor (PR), were detected immunohistochemically. ER expression was not different in <jats:italic>BRCA<\/jats:italic> mutation carriers than in noncarriers, but there was a reduction in PS2 expression. PR expression was also reduced, and there was a striking lack of expression of the PRB isoform, which resulted in cases with PRA\u2010only expression in <jats:italic>BRCA1<\/jats:italic> and <jats:italic>BRCA2<\/jats:italic> mutation carriers. The alterations in PS2 and PR expression were similar in the <jats:italic>BRCA1<\/jats:italic> and <jats:italic>BRCA2<\/jats:italic> carriers, demonstrating that although these proteins are structurally and functionally distinct, there is overlap in their interaction with hormone\u2010signaling pathways. This study provides evidence for altered cell function arising from loss of function of one <jats:italic>BRCA<\/jats:italic> allele in the normal breast, leading to PS2 loss, preferential PRB loss, and expression of PRA alone. In breast cancer development, PRA overexpression becomes evident in premalignant lesions and is associated with features of poor prognosis in invasive disease and altered cell function in vitro. The results of this study suggest that heterozygosity for a germ\u2010line mutation in <jats:italic>BRCA1<\/jats:italic> or <jats:italic>BRCA2<\/jats:italic> results in development of PRA predominance. This is likely to lead to changes in progesterone signaling in hormone\u2010dependent tissues, which may be a factor in the increased risk of cancer in these tissues in women with germ\u2010line <jats:italic>BRCA1<\/jats:italic> or <jats:italic>BRCA2<\/jats:italic> mutations. \u00a9 2004 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/gcc.10321","type":"journal-article","created":{"date-parts":[[2004,1,15]],"date-time":"2004-01-15T10:01:18Z","timestamp":1074160878000},"page":"236-248","source":"Crossref","is-referenced-by-count":84,"title":["Germ\u2010line mutations in <i>BRCA1<\/i> or <i>BRCA2<\/i> in the normal breast are associated with altered expression of estrogen\u2010responsive proteins and the predominance of progesterone receptor A"],"prefix":"10.1002","volume":"39","author":[{"given":"Patricia A.","family":"Mote","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer 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