Both ovarian hormones estrogen and progesterone are necessary for hormonal mammary carcinogenesis in ovariectomized ACI rats

Abstract

August-Copenhagen-Irish (ACI) rats are unique in that the ovaryintact females develop high incidence of mammary cancers induced solely by hormones upon prolonged exposure to high levels of estrogen alone. Studies have also shown that such prolonged exposure to high-dose estrogen results in human-like aneuploid mammary cancers in ovary-intact ACI rats. To determine the role of progesterone in mammary carcinogenesis, six-week-old intact and ovariectomized ACI rats were continuously exposed to low-and high-dose estrogen alone, progesterone alone, low-dose estrogen plus progesterone, and ovariectomized ACI rats with high-dose estrogen plus progesterone. Also, ovariectomized ACI rats were treated with high-dose estrogen plus progesterone plus testosterone to determine the role of the androgen, testosterone, if any, in hormonal mammary carcinogenesis. The results indicate that continuous exposure to high, but not low, concentrations of estrogen alone can induce mammary carcinogenesis in intact but not in ovariectomized rats. Mammary carcinogenesis in ovariectomized ACI rats requires continuous exposure to high concentrations of estrogen and progesterone. The addition of testosterone propionate does not affect tumor incidence in such rats. These results suggest that both ovarian hormones estrogen and progesterone are necessary for mammary carcinogenesis induced solely by hormones in ovariectomized ACI rats. Our results are in agreement with the Women's Health Initiative studies, where treatment of postmenopausal women with estrogen (ERT) alone did not increase the risk of breast cancer, but estrogen and progesterone (HRT) did. I n women, breast cancer is the most prevailing endocrine-related malignancy (1), and epidemiological studies argue that estrogens (E) are central to its etiology (2). Most of what we know regarding the role of ovarian hormones in human breast carcinogenesis is based primarily on epidemiological (2) and animal studies with mice carrying mammary tumor virus or treated with chemical carcinogen (see ref.3) and/or rats treated with chemical carcinogens (4-6). The Women's Health Initiative studies showed increased breast cancer risk in postmenopausal women treated with estrogen and progesterone (HRT) (7) but not in postmenopausal women treated with estrogen (ERT) alone (8). Although E has historically been the focus of breast cancer etiology, it is clear that this E effect must be viewed in context of the entire woman or animal. However, the possible role of progesterone (P), if any, as the other main ovarian hormone in mammary carcinogenesis is essential for the understanding of breast cancer biology and its prevention. Progesterone receptor (PR) depends on the presence of E for its expression (9-11). E has been regarded as an initiator (12) and promoter (13, 14) of breast cancer. P has also been thought as a promoter (15) of breast cancer. E has also been thought to induce mammary carcinogenesis via the mitogenesis-mutagenesiscarcinogenesis route (16-18) through centrosome disturbance via aurora kin...

PTEN/PIK3CA genes are frequently mutated in spontaneous and medroxyprogesterone acetate-accelerated 7,12-dimethylbenz(a)anthracene-induced mammary tumours of tree shrews

“…DMBA is a commonly used breast targeted carcinogen in rodents by intragastric administration [24,38], and it seemed to work somewhat in our tree shrew groups, as DMBA induced one intraductal papilloma in subject #30. Other evidence has suggested that progestin increased the risk of breast cancer in women [39,40], and progesterone and its derivative MPA have been shown to be sufficient in including mammary carcinomas among rodents [41][42][43], cats and dogs [44]. Furthermore, MPA has also been shown to accelerate DMBA-induced breast tumour development in both rats [45] and mice [15,24,46].…”

Prolactin and estradiol utilize distinct mechanisms to increase serine-118 phosphorylation and decrease levels of estrogen receptor α in T47D breast cancer cells

“…Evidence also suggests that exposure to increased levels of these hormones increases the risk for breast cancer [1][2][3][4][5]. However, relatively little is known about how E2 and PRL interact at the level of mammary epithelium.…”

Prevention of Oxidative DNA Damage by Bioactive Berry Components

“…Akin to the human scenario, high levels of circulating E 2 causes mammary tumors in these rats (14,15). Both progesterone and estradiol are required for the development of tumors (16). E 2 causes DNA and epigenetic damage in the mammary (17,18), and blocking of E 2 metabolizing enzymes or estrogen receptors abrogate the tumorigenesis (19).…”