Expression of AP-2 transcription factors in human breast cancer correlates with the regulation of multiple growth factor signalling pathways.
The AP-2 transcription factors are required for normal growth and morphogenesis during mammalian development. Previous in vitro studies have also indicated that the AP-2 family of proteins may be involved in the etiology of human breast cancer. The AP-2 genes are expressed in many human breast cancer cell lines, and critical AP-2-binding sites are present in both the ERBB-2 (HER2/neu) and estrogen receptor promoters. We have now characterized immunological reagents that enable specific AP-2 family members, including AP-2alpha and AP-2gamma, to be detected in human breast cancer epithelium. Data obtained with these reagents demonstrate that whereas AP-2alpha and AP-2gamma are both present in benign breast epithelia, there is a significant up-regulation of AP-2gamma expression in breast cancer specimens (P = 0.01). There was also a significant correlation between the presence of the AP-2alpha protein and estrogen receptor expression (P = 0.018) and between specimens containing both AP-2alpha/AP-2gamma proteins and ERBB-2 expression (P = 0.003). Furthermore, we detected an association (P = 0.04) between the expression of AP-2gamma and the presence of an additional signal transduction molecule implicated in breast cancer, the insulin-like growth factor I receptor. Analysis of the proximal promoter of the insulin-like growth factor I receptor revealed a novel AP-2-binding site. Thus, AP-2 proteins may directly regulate the transcription of this growth factor receptor. Taken together, these data strongly support a role for the AP-2 gene family in the control of cell growth and differentiation in breast cancer.
Turner
B C
BC
Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut 06511, USA.
Zhang
J
J
Gumbs
A A
AA
Maher
M G
MG
Kaplan
L
L
Carter
D
D
Glazer
P M
PM
Hurst
H C
HC
Haffty
B G
BG
Williams
T
T
D001665:Binding Sites; D001940:Breast / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D004848:Epithelium / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000502:physiology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis; D017526:Receptor, IGF Type 1 / Q000235:genetics; D011960:Receptors, Estrogen / Q000096:biosynthesis; D017978:Receptors, Growth Factor / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011980:Receptors, Progesterone / Q000096:biosynthesis; D015398:Signal Transduction / Q000502:physiology*; D050656:Transcription Factor AP-2; D014157:Transcription Factors / Q000096:biosynthesis*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000502:physiology
D004268:DNA-Binding Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D017526:Receptor, IGF Type 1; D011960:Receptors, Estrogen; D017978:Receptors, Growth Factor; D011980:Receptors, Progesterone; D050656:Transcription Factor AP-2; D014157:Transcription Factors; C493673:TFAP2A protein, human; C493679:TFAP2C protein, human