Lydon J P, Ge G, Kittrell F S, Medina D, O'Malley B W
Department of Cell Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Cancer Res. 1999 Sep 1;59(17):4276-84.
To define the functional relevance of progesterone-initiated intracellular signaling in mammary gland tumorigenesis, the progesterone receptor knockout (PRKO) mouse model was used in the context of an established carcinogen-induced mammary tumorigenesis system. In carcinogen-treated, 7,12-dimethylbenz(a)anthracene (DMBA), pituitary-isografted mice, there was a marked reduction 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 carcinogen administration, the proliferative index of the pituitary-stimulated WT gland was at least 4-fold higher than similarly treated PRKO glands, supporting 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-initiated mammary tumors observed in the PRKO were assumed to be exclusively of ductal origin. Compared with previous tested strains, by 47 weeks, a higher incidence of DMBA-induced ovarian tumors was observed in this mouse strain: (a) 4 (20%) of 20 WT mice and 9 (45%) of 20 PRKO mice with a pituitary isograft; and (b) 10 (50%) of 20 WT mice and 10 (50%) of 20 PRKO mice without a pituitary isograft. Despite the host-strain's underlying propensity for DMBA-induced ovarian neoplasms, our studies underscore the specific importance of the PR (as distinct from the estrogen receptor) as a mandatory mediator for those intracellular signaling pathways that are essential for the initiation of the majority of murine mammary tumors induced by DMBA. Apart from providing strong support for progesterone's role in mammary gland tumorigenesis as well as furthering our fundamental understanding of breast cancer etiology, these studies may have implications for the routine use of progestins.
为了确定孕酮启动的细胞内信号传导在乳腺肿瘤发生中的功能相关性，在已建立的致癌物诱导的乳腺肿瘤发生系统中使用了孕酮受体敲除（PRKO）小鼠模型。在经致癌物处理的垂体同种异体移植的7,12-二甲基苯并(a)蒽（DMBA）小鼠中，与同基因野生型（WT）相比，PRKO小鼠的乳腺肿瘤发生率显著降低。在首次DMBA处理后44周，20只WT小鼠中有12只（60%）出现乳腺肿瘤，而20只PRKO小鼠中只有3只（15%）出现。在没有垂体同种异体移植的情况下，到47周时，20只WT小鼠中有4只（20%）出现乳腺肿瘤，20只PRKO小鼠中有4只（20%）出现。在给予致癌物时，垂体刺激的WT腺体的增殖指数比同样处理的PRKO腺体至少高4倍，这支持了PR介导的增殖途径在这种肿瘤类型发生中的重要性。与WT腺体不同，PRKO腺体在垂体同种异体移植刺激下不能表现出腺泡形成；因此，在PRKO中观察到的DMBA引发的乳腺肿瘤被认为完全起源于导管。与先前测试的品系相比，到47周时，在该小鼠品系中观察到更高的DMBA诱导的卵巢肿瘤发生率：（a）有垂体同种异体移植的20只WT小鼠中有4只（20%），20只PRKO小鼠中有9只（45%）；（b）没有垂体同种异体移植的20只WT小鼠中有10只（50%），20只PRKO小鼠中有10只（50%）。尽管宿主品系有DMBA诱导卵巢肿瘤的潜在倾向，但我们的研究强调了PR（与雌激素受体不同）作为大多数由DMBA诱导的小鼠乳腺肿瘤起始所必需的细胞内信号传导途径的强制性介质的特殊重要性。除了为孕酮在乳腺肿瘤发生中的作用提供有力支持以及加深我们对乳腺癌病因的基本理解外，这些研究可能对孕激素的常规使用有影响。
