A 28-amino-acid peptide fragment of the cupredoxin azurin prevents carcinogen-induced mouse mammary lesions.
Azurin, a member of the cupredoxin family of redox proteins, preferentially penetrates human cancer cells and exerts cytostatic and apoptotic effects. Azurin and amino acids 50-77 (p28) of azurin also produce a dose-dependent reduction in the proliferation of human mammary cancer by increasing the level of the tumor suppressor protein p53 in the cancer cell nucleus. We show that the development of 7,12-dimethylbenz[a]anthracene-induced hormone-dependent premalignant mammary ductal lesions and hormone-independent mammary alveolar lesions in mouse mammary gland organ culture is also significantly reduced by azurin and p28. The dose-dependent reduction in carcinogen-induced mammary cell proliferation by p28 was associated with an increase in the expression of p53. p28 also enhanced the inhibitory effect of a low dose of the antiestrogen tamoxifen on the development of hormone-dependent mammary ductal lesions, but did not enhance the inhibitory activity of fenretinide (N-4-hydroxyphenyl retinamide) on hormone-independent mammary alveolar lesions. These observations suggest that cupredoxins and fragments derived from them can exert a chemopreventive effect on carcinogen-induced mammary gland transformation, irrespective of hormonal environment, and enhance the inhibitory effects of tamoxifen in this model of preneoplastic mammary development.
Mehta
Rajeshwari R
RR
Department of Surgical Oncology, University of Illinois, Chicago, IL 60612, USA.
Hawthorne
Michael
M
Peng
Xinjian
X
Shilkaitis
Ann
A
Mehta
Rajendra G
RG
Beattie
Craig W
CW
Das Gupta
Tapas K
TK
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001400:Azurin / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D007150:Immunohistochemistry; D008325:Mammary Neoplasms, Experimental / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D010446:Peptide Fragments / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013629:Tamoxifen / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000970:Antineoplastic Agents; D010446:Peptide Fragments; D016159:Tumor Suppressor Protein p53; D013629:Tamoxifen; D001400:Azurin