Sex hormone-induced mammary carcinogenesis in the female Noble rats: expression of bcl-2 and bax in hormonal mammary carcinogenesis.
We have established a Noble rat model to explore the mechanisms of hormonal mammary carcinogenesis, in which the role of androgen in promoting mammary carcinogenesis was highlighted. We have also established that stromal-epithelial interactions may be responsible for the promotional effects of testosterone in mammary carcinogenesis. Based on these understandings, in the present study we examined the expression of Bcl-2 and Bax in pre-malignant mammary glands from rats treated with different protocols of sex hormones for 7 weeks as well as sex hormone induced mammary tumours. We observed that Bcl-2 was strongly expressed in most of mammary tumour cells, whereas weak or negative in adjacent normal or hyperplastic ductal structures. On the contrary, Bax immunoreactivity was weak in mammary tumour cells while strongly expressed in adjacent normal or hyperplastic ductal structures. More importantly, the results from comparative study of 'pre-malignant' glands further showed that when animals were treated with 17beta-oestradiol, the mammary epithelial cells expressed high levels of Bcl-2. The results from rats treated with testosterone, either alone or in combination with oestrogen, give rise to high levels of Bax expression in 'pre-malignant' mammary glands. These observations indicate that in 'pre-malignant' mammary glands, treatment with testosterone, either alone or in combination with 17beta-oestradiol, may induce high apoptotic activities. However, in fully developed mammary tumours, the apoptotic activities apparently decrease in tumour cells. TUNEL assay provides further data to support this conclusion. Our study, thus, suggests that androgens may play a promoting role in mammary carcinogenesis by upregulation of Bax expression and induction of high apoptotic activities in 'pre-malignant' stage, which would provide a selective pressure favouring the expansion of the initiated cells.
Xie
B
B
Department of Anatomy, Faculty of Medicine, University of Hong Kong, Hong Kong.
Tsao
S W
SW
Wong
Y C
YC
D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis; D001940:Breast / Q000378:metabolism; D004195:Disease Models, Animal; D004958:Estradiol; D005260:Female; D012739:Gonadal Steroid Hormones; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008325:Mammary Neoplasms, Experimental / Q000209:etiology* / Q000378:metabolism; D009376:Neoplasms, Hormone-Dependent / Q000209:etiology* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D011897:Random Allocation; D051381:Rats; D011919:Rats, Inbred Strains; D011944:Receptors, Androgen / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D013739:Testosterone; D051028:bcl-2-Associated X Protein
C494828:Bax protein, rat; D012739:Gonadal Steroid Hormones; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011944:Receptors, Androgen; D011960:Receptors, Estrogen; D051028:bcl-2-Associated X Protein; D013739:Testosterone; D004958:Estradiol