REFRACTORINESS TO MAMMARY CARCINOGENESIS IN THE PAROUS MOUSE IS REVERSIBLE BY HORMONAL-STIMULATION INDUCED BY PITUITARY ISOGRAFTS

We have previously reported that mouse mammary epithelial cells transf ormed in vitro yield tumors which vary qualitatively and quantitativel y as a function of the mitogenic environment in which the cells are pr opagated at the time of carcinogen treatment. One milieu supportive of transformation in vitro was medium supplemented with progesterone and prolactin as the mitogens. We have performed parallel studies in whic h virgin mice were isografted with pituitaries resulting in elevated s erum titers of progesterone and prolactin. After carcinogen treatment, these mice developed mammary tumors which included those identical ge notypically and phenotypically to tumors induced in vitro in cells gro wn in progesterone and prolactin during carcinogen exposure. Our curre nt working hypothesis is that the mitogenic environment around the tim e of carcinogen administration can modulate the incidence and phenotyp e of the resultant tumors. To further test this hypothesis, we have ev aluated the susceptibility of hormonally-stimulated parous mice to che mically induced mammary carcinogenesis since parity is known to signif icantly reduce the susceptibility of the mouse mammary gland to carcin ogenesis. Virgin or multiparous BALB/c mice were isografted with two p ituitaries. Five weeks after surgery, the mice were injected with N-me thyl-N-nitrosourea (MNU; 50 mu g/g i.v.). Mammary carcinomas arose in 85% (11/13) with a median latency of 22.8 weeks and 1.9 tumors per vir gin mouse and 80% (24/30) with a median latency of 22.1 weeks at a fre quency of 1.9 tumors per parous mouse. Only 14% (2/14) of the non-isog rafted, age-matched parous controls developed tumors when injected wit h MNU. Fourteen parous mice receiving only pituitary isografts (no MNU ), did not develop mammary carcinomas within the 7-month period of the study. These results demonstrate that parous BALB/c mice are refracto ry to MNU-induced mammary carcinogenesis and that this refractoriness is not permanent, but can be overcome by hormonal stimulation mediated by pituitary isografts.