Hormone dependence in premalignant mammary progression

Human breast cancers that are estrogen receptor (ER) negative convey a poor prognosis for patient survival. A mouse model that mimics essential biological and genetic attributes of a subset of human breast cancer is the BALB/c p53-null mammary epithelium, in which deletion of the tumor suppressor gene p53 results in enhanced tumorigenic risk. The experiments reported herein examine the hormone dependence of premalignant mammary progression in this model. The p53-null normal mammary epithelium exhibits the same dependence as p53 wild-type mammary epithelium on ovarian hormones for growth. However, in contrast to p53 wild-type epithelium, estrogen and progesterone, singly or in combination, strongly enhance tumorigenesis in p53-null mammary epithelium. The removal of progesterone signaling by deletion of the progesterone receptor eliminates progesterone enhancement of tumorigenesis. The immortalized premalignant outgrowth lines, termed PN, possess different tumorigenic capabilities, but the majority of these lines showed a strong dependence on ovarian hormones for growth and tumorigenesis. Although these lines are highly ER positive, a large number of tumors arising from these lines were ER negative and grew when implanted in ovariectomized mice. As was the case for p53-null normal mammary cells, hormonal stimulation was a strong promoter for tumorigenesis in the premalignant outgrowth lines and, surprisingly, was much stronger than the chemical carcinogen 7,12-dimethylbenzanthracene. In summary, these results demonstrate that p53-null mammary cells, which generate a significant percentage of ER-negative tumors, are highly responsive to the absence or presence of ovarian hormones during the normal and premalignant stages. This model would appear an excellent one to test the effects of chemopreventive agents on the development of both ER-negative and ER-positive mammary tumors.