EXPRESSION OF A TRUNCATED INT3 GENE IN DEVELOPING SECRETORY MAMMARY EPITHELIUM SPECIFICALLY RETARDS LOBULAR DIFFERENTIATION RESULTING IN TUMORIGENESIS

Insertional mutation of the Int3 gene, a member of the Notch gene fami ly, is frequently associated with primary mouse mammary tumors induced by the mouse mammary tumor virus (MMTV). A major consequence of these mutations Is the production of a shortened 2,4-kb tumor-specific Int3 RNA transcript that encodes the entire intracellular domain of the In t3 protein, Previous studies have demonstrated that mammary gland deve lopment and function was severely impaired in transgenic mice expressi ng the truncated Int3 gene product from the MMTV viral promoter, Both mammary ductal growth and secretory lobule development were curtailed in these mice, These results were attributed to a gain of function mod ification of the Int3 gene, which led to a restriction of cell fate se lection in the affected mammary epithelial cells, To confirm and exten d these findings, truncated Int3 was expressed from the whey acidic pr otein (WAP) promoter, the activity of which, unlike that of the MMTV l ong terminal repeat, is restricted to the secretory mammary epithelial population, In transgenic mice carrying the WAP/Int3 construct, mamma ry ductal growth was unaffected in virgin females, but growth and diff erentiation of secretory lobules during gestation was profoundly inhib ited, Coincidental with the block in lobular secretory differentiation , mammary dysplasia and tumorigenesis occurred in all breeding females by 25 weeks of age, In nonbreeding WAP/Int3 females, mammary tumor in cidence also reached 100%, but only after 70 weeks. The WAP/Int3 mamma ry tumors were highly malignant, and most tumor-bearing females, irres pective of breeding history, developed metastatic lung lesions, These results suggest that WAP promoter-targeted Int3 function is associated with mammary secretory cell differentiation and maintenance in this t ransgenic model, Consistent with the conclusion that WAP-driven trunca ted Int3 expression influenced only lobular differentiation and not du ctal growth and extension during mammary gland development, transplant s of I VAP/Int3 gland into nontransgenic mammary fat pads produced com plete mammary ductal outgrowths in virgin FVB/N mice but failed to dev elop secretory lobules when the females were impregnated.