FUNCTIONAL-ANALYSIS OF MOUSE KERATIN-8 IN POLYOMA MIDDLE-T-INDUCED MAMMARY-GLAND TUMORS

Keratin 8 and 18 are commonly used as tumorigenic markers for various types of carcinomas. They are known to be involved in cell migration, cell invasiveness, plasminogen activity and drug and radiation resista nce. To ascertain a potential function for simple epithelium keratins in mammary adenocarcinoma in vivo, keratin-8-deficient mice (mK8) were mated with transgenic mice carrying the middle T oncogene driven by t he MMTV promoter. The resulting mK8 knockout and control progeny carry ing the middle T transgene developed mammary gland tumours with the sa me incidence. However, the onset of palpable mammary gland tumours occ urred earlier in mK8 mutant than in control mice. This effect was prom inent in males where the onset in control animals is delayed overall, because of the lower hormonal inducibility of the MMTV promoter. Metas tatic foci were observed in the lungs of all females and of a few male s, independently of the genotype. Histological analysis revealed no mo rphological differences of the tumorigenic cells in primary tumours no r in metastatic foci. As expected, keratin 8 was absent in the mK8 tum ours. Keratin 7 (mK7), keratin 18 (mK18) and keratin 19 (mK19) protein were observed in both primary and metastatic foci. These results cons titute the first in vivo analysis of the role of simple epithelium ker atins in mammary carcinogenesis. It demonstrates that the latency, but not the incidence nor the morphological features, of PyV middle T-ind uced mammary gland tumours is affected by keratin 8 deficiency.