Cytogenetic findings, Trp53 mutations, and hormone responsiveness in a medroxyprogesterone acetate induced murine breast cancer model.

ABSTRACT

Medroxyprogesterone acetate (MPA)-induced mammary carcinomas express high levels of estrogen (ER) and progesterone receptors (PR) and when transplanted in syngeneic mice they show a progestin-dependent (PD) growth pattern. By successive transplantation, progestin-independent (PI) variants were generated and showed a different response to antihormone therapy. A diploid chromosome number (2n=40) was found in three of five PD tumors, with numbers in the triploid to tetraploid range in the other two. Some PI tumors were diploid, but most were aneuploid (8 of 12 tumors). The most frequent alterations found in PD and PI tumors were gains of chromosomes 3, 4, and 6 and losses of chromosomes 16 and X. Chromosomes 4 and 7 were involved in translocations in three of the four tumor families studied. single-strand conformation polymorphism analysis revealed a point mutation on the Trp53 gene in one of the PD tumors; this showed a stable diploid karyotype, suggesting that mutated Trp53 is not uniquely involved in chromosome instability. We have shown that hormone independence may be acquired without changes in ploidy, suggesting that the increase in ploidy is favored by successive transplantation. In our model, diploid tumors responded to hormone treatment but aneuploid tumors were either responsive or not.