HOXA5 regulates expression of the progesterone receptor.
The majority of breast carcinomas show reduced or no expression of the transcription factor, HOXA5. Recently, we have shown that HOXA5 is a potent transactivator of p53 in breast cells and thus may affect the response of breast cancer cells to DNA damage. To determine whether HOXA5 played a role in growth and homeostasis in breast cells, we studied its interaction with the progesterone receptor. The progesterone receptor (PR) belongs to the superfamily of nuclear receptors whose members co-ordinate morphogenesis of the mammary gland in response to binding to their cognate ligands. An increased expression of the endogenous PR gene was seen in MCF-7 cells following induced expression of an exogenously transfected HOXA5 gene. HOXA5, but not HOXB4, -B5, or -B7 activated the PR promoter in two breast cancer cell lines, MCF-7 and Hs578T. Deletion and mutation analysis of the promoter identified a single HOXA5-binding site required for transactivation of the PR gene by HOXA5. HOXA5 binds directly to this site in the PR promoter. Thus, HOXA5 may behave as a transcriptional regulator of multiple target genes, two among which are p53 and the progesterone receptor.
Raman
V
V
Breast Cancer Program, Johns Hopkins Oncology Center, Baltimore, Maryland 21231, USA.
Tamori
A
A
Vali
M
M
Zeller
K
K
Korz
D
D
Sukumar
S
S
D001483:Base Sequence; D001665:Binding Sites; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D018398:Homeodomain Proteins / Q000502:physiology*; D006801:Humans; D008156:Luciferases / Q000235:genetics; D008969:Molecular Sequence Data; D010750:Phosphoproteins / Q000502:physiology*; D011980:Receptors, Progesterone / Q000096:biosynthesis* / Q000235:genetics; D014157:Transcription Factors / Q000502:physiology*; D014407:Tumor Cells, Cultured
C489213:HOXA5 protein, human; D018398:Homeodomain Proteins; D010750:Phosphoproteins; D011980:Receptors, Progesterone; D014157:Transcription Factors; D008156:Luciferases