Induction of apoptosis in mammary gland by a pure anti-estrogen ICI 182780.
The antiestrogen, ICI 182780 (ICI) proves to be clinically useful for the treatment of estrogen receptor positive breast tumours. We report the assessment of the in vivo and in vitro effects of ICI on apoptosis of breast epithelial cells. In vivo, administration of rats with ICI for 3 weeks resulted in a reduction in the size of the lobular structures with the rate of mammary epithelial apoptosis equivalent to 10, 35 and 45% on treatment with 1, 1.5 and 2 mg ICI per kg body weight, respectively. Concomitantly, these treatment led to a 2.0-, 2.2- and 2.5-fold increase in Bax. Similar elevations were also observed in Bad levels which increased 1.7-, 2.6- and 2.7-fold respectively in the ICI treatment as compared to controls. This also resulted in a dose dependent decrease in Bcl-2 and Bcl-xL protein expressions. Growth inhibition and induction of apoptosis were also observed in the MCF-7 cells following in vitro treatment with ICI. This is closely associated with [1] the down-regulation of Bcl-2 and Bcl-xL proteins and [2] upregulation of Bax and Bad, whose gene products are known to be involved the regulation of apoptosis in mammalian cells. Stable over-expression of Bcl-2 resulted in protection of MCF-7 cells from apoptosis and growth inhibitory effects of ICI. Conversely, reduction of Bcl-2 by antisense transfection make MCF-7 cells more sensitive to ICI-induced growth inhibition and apoptosis. These findings suggest that modulation of Bax, Bcl-xL, Bcl-2 and Bad proteins by ICI may be, in part, responsible for the anti-proliferative and apoptotic effect of ICI seen clinically and in animal models.
Lim
K B
KB
Division of Cellular and Molecular Research, National Cancer Centre of Singapore, Singapore.
Ng
C Y
CY
Ong
C K
CK
Ong
C S
CS
Tran
E
E
Nguyen
T T
TT
Chan
G M
GM
Huynh
H
H
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology*; D005260:Female; D000077267:Fulvestrant; D015870:Gene Expression; D006801:Humans; D007124:Immunoenzyme Techniques; D020287:In Situ Nick-End Labeling; D019394:Ki-67 Antigen / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein
C494819:BAD protein, human; C494826:BAX protein, human; C494811:BCL2L1 protein, human; C494821:Bad protein, rat; C494828:Bax protein, rat; C494813:Bcl2l1 protein, rat; D002352:Carrier Proteins; D004965:Estrogen Antagonists; D019394:Ki-67 Antigen; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein; D000077267:Fulvestrant; D004958:Estradiol