Murine mammary gland carcinogenesis is critically dependent on progesterone receptor function

To define the functional relevance of progesterone-initiated intracellular signaling in mammary gland tumorigenesis, the progesterone receptor knockou t (PRKO) mouse model was used in the context of an established carcinogen-i nduced mammary tumorigenesis system. In carcinogen-treated, 7,12-dimethylbe nz(a)anthracene (DMBA), pituitary-isografted mice, there was a marked reduc tion in mammary tumor incidence in PRKO mice as compared with isogenic wild types (WT). Mammary tumors arose in 12 (60%) of 20 WT mice compared with 3 (15%) of 20 PRKO mice by 44 weeks after the initial DMBA treatment, In the absence of a pituitary isograft, mammary tumors developed in 4 (20%) of 20 WT mice versus 4 (20%) of 20 PRKO mice by 47 weeks, At the time of carcino gen administration, the proliferative index of the pituitary-stimulated WT gland was at least 4-fold higher than similarly treated PRKO glands, suppor ting the importance of PR-mediated proliferative pathways in the genesis of this tumor type. Unlike the WT gland, the PRKO gland was unable to exhibit alveologenesis in response to pituitary isograft stimulation; thus, DMBA-i nitiated mammary tumors observed in the PRKO were assumed to be exclusively of ductal origin. Compared with previous tested strains, by 47 weeks, a hi gher incidence of DMBA-induced ovarian tumors was observed in this mouse st rain: (a) 4 (20%) of 20 WT mice and 9 (45%) of 20 PRKO mice with a pituitar y isograft; and (b) 10 (50%) of 20 WT mice and 10 (50%) of 20 PRKO mice wit hout a pituitary isograft, Despite the host-strain's underlying propensity for DMBA-induced ovarian neoplasms, our studies underscore the specific imp ortance of the PR las distinct from the estrogen receptor) as a mandatory m ediator for those intracellular signaling pathways that are essential for t he initiation of the majority of murine mammary tumors induced by DMBA. Apa rt from providing strong support for progesterone's role in mammary gland t umorigenesis as well as furthering our fundamental understanding of breast cancer etiology, these studies may have implications for the routine use of progestins.