Oestrogen receptor gene structure and function in breast cancer.
The mechanisms underlying loss of oestrogen responsiveness in breast cancer are not well-defined. Potential mechanisms include loss of receptor expression, alterations in the oestrogen receptor (ER) gene producing proteins with abnormal function, or changes to receptor-dependent or -independent pathways controlling cell proliferation. Examination by Southern analysis of the ER gene in a series of ER-negative and -positive breast tumour biopsies failed to provide evidence of gross rearrangements and in only one of thirty seven tumour DNA samples was significant gene amplification observed. No restriction fragment length polymorphisms were detected for the restriction enzymes EcoR I, Pst I or Hind III. Methylation of the ER gene as assessed by Hpa II and Msp I restriction enzyme digests varied between tumours but the degree of methylation was not correlated with levels of expression of the receptor protein. Similar findings applied in a series of ER-negative and -positive breast cancer cell lines and clonal lines of MCF-7 cells, which were developed as an in vitro model for the acquisition of oestrogen and antioestrogen resistance. In this model there was no evidence that changes to ER receptor function and/or structure at the level of the ER gene, mRNA, ligand binding, and ability to induce progesterone receptor might account for the development of hormone resistance. However, the ability of ER to interact with a DNA sequence containing the vitellogenin promoter oestrogen response element, as assessed by gel retardation assay, was impaired in the clone showing the greatest degree of oestrogen and antioestrogen resistance.
Watts
C K
CK
Cancer Biology Division, Garvan Institute of Medical Research, St Vincent's Hospital, Sydney, NSW, Australia.
Handel
M L
ML
King
R J
RJ
Sutherland
R L
RL
D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002999:Clone Cells; D004273:DNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D006801:Humans; D008969:Molecular Sequence Data; D011960:Receptors, Estrogen / Q000235:genetics* / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid; D015183:Restriction Mapping; D013629:Tamoxifen / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D004273:DNA, Neoplasm; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D013629:Tamoxifen; D004958:Estradiol