Targeted production of proprotein convertase PC1 enhances mammary development and tumorigenesis in transgenic mice.
Elevated production of proprotein convertases (PCs), proteolytic enzymes that posttranslationally modify the biological activities of diverse groups of cellular proteins, is a common occurrence in human breast carcinomas. A transgenic mouse model was developed to gain insight into the significance of PC production in breast development and neoplasia. Mammary epithelium-specific and early expression of PC1 was targeted by the use of the mouse mammary tumor virus promoter/enhancer. Whole-mount examinations revealed that the mammary glands of 83-day-old virgin PC1 transgenic mice exhibited an accelerated lobuloalveolar development compared with that of age-matched wild-type mice (p < 0.001). This phenotypic change was accompanied by extensive alterations in gene expression assessed by gene expression microarray analyses. Pathway analysis of PC1-induced alterations in gene expression has revealed possible mechanism of action of PC1 in the mammary gland. PC1 expression alone, however, did not promote spontaneous mammary tumorigenesis in the transgenic mice. PC1 transgene expression resulted in a significantly higher incidence (p = 0.008) and accelerated growth (p = 0.023) of 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary adenocarcinomas. The present study therefore shows that PC1 expression can promote normal and neoplastic mammary development and growth and suggests that proprotein convertases may be important etiological factors in human breast neoplasia.
Blanchard
Anne
A
Department of Physiology, University of Manitoba, Winnipeg, MB R3E 0W3, Canada.
Iwasiow
Barbara
B
Yarmill
Alison
A
Fresnosa
Agnes
A
Silha
Josef
J
Myal
Yvonne
Y
Murphy
Leigh C
LC
Chrétien
Michel
M
Seidah
Nabil
N
Shiu
Robert P C
RP
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D015153:Blotting, Western; D002273:Carcinogens / Q000633:toxicity; D018076:DNA, Complementary / Q000235:genetics; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008321:Mammary Glands, Animal / Q000254:growth & development* / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D045664:Proprotein Convertase 1 / Q000096:biosynthesis* / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D002273:Carcinogens; D018076:DNA, Complementary; D015127:9,10-Dimethyl-1,2-benzanthracene; D045664:Proprotein Convertase 1