AP-2 transcription factors in the regulation of ERBB2 gene transcription by oestrogen

Transcription of the ERBB2 oncogene is repressed by oestrogen in human brea st cancer cells. We show that a 218 bp fragment of the human ERBB2 gene pro moter is responsive to oestrogen in transient transfection in ZR75.1 and SK BR.3 cells when the oestrogen receptor is expressed. Deletion analysis of t his fragment shows that a sequence located at the 5' end, which is known to mediate ERBB2 overexpression in breast cancer, is also responsible for the oestrogen response. This sequence binds AP-2 transcription factors and app ears functionally identical to an element of the oestrogen-dependent enhanc er described in the first intron of human ERBB2, We observed that oestrogen treatment down-regulates expression of AP-2 proteins but does not affect t he DNA binding activity of AP-2. Constitutive expression of AP-2 beta or AP -2 gamma, but not AP-2 alpha, abrogates the estrogenic repression. Our resu lts demonstrate that AP-2 transcription factors are implicated in the oestr ogenic regulation of ERBB2 gene expression and suggest a complex interplay involving the different AP-2 isoforms and other unidentified factors.