Prevention of solely estrogen-induced mammary tumors in female aci rats by tamoxifen: evidence for estrogen receptor mediation

Li, Sa; Sj, Weroha; Tawfik, Ossama; Jj, Li

doi:10.1677/joe.0.1750297

Cited by 60 publications

(48 citation statements)

References 39 publications

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“…Similar centrosome amplification has been observed in a well-characterized rat mammary tumor model where animals were exposed to methylnitrosourea (Sivaraman et al 1998). Female August/ Copenhagen/Irish (ACI) rats treated with physiological levels of 17b-estradiol (E 2 ) developed mammary gland tumors with characteristics similar to those in ductal carcinoma in situ (DCIS) and invasive sporadic ductal breast cancer (Li et al 2002). Prolonged treatment of estrogen in these rats for 4 months caused centrosomal abnormalities, aneuploidy generated by random and non-random chromosome changes and upregulation of key molecules such as myc and Aurora-A (Li et al 2004).…”

Section: Introductionsupporting

confidence: 53%

Downregulation of Aurora-A overrides estrogen-mediated growth and chemoresistance in breast cancer cells

Lee¹,

Zhu²,

Govindasamy³

et al. 2008

Endocrine Related Cancer

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Estrogen is known to play a causative role in the development of sporadic breast cancers and chemoresistance. However, studies on the mechanism and proteins involved in mediating the oncogenic effects of estrogen are very limited. Recently, Aurora-A, a centrosomal protein kinase, which induces centrosome amplification and genomic instability, has been shown to be upregulated during long-term treatment of rats with estrogen and was implicated in estrogen-induced oncogenesis. Herein, we present results of the studies carried out in short-term in vitro cultures to understand the regulation of Aurora-A by estrogen and the effect of downregulation of Aurora-A on estrogen-induced breast tumorigenesis and chemoresistance. Treatment of breast cancer cells with 10 nM 17b-estradiol (E 2 ) resulted in the upregulation of Aurora-A levels in an estrogen receptordependent manner. However, the upregulation by E 2 was not restricted to Aurora-A alone. Following release from the tamoxifen-induced arrest, the appearance of Aurora-A in the presence of estradiol in MCF7 cells coincided with the appearance of other mitotic markers suggesting that the spike in Aurora-A levels is an indirect consequence of estrogen-mediated cell proliferation. Thus, at least in short-term in vitro studies, Aurora-A is not a specific direct target of estrogen. However, downregulation of Aurora-A by RNA interference led to a significant decrease in estrogen-induced, anchorage-dependent, and independent growth of MCF7 cells. Moreover, knockdown of Aurora-A could overcome estrogen-induced decrease in docetaxel sensitivity of MCF7 cells. Cumulatively, we propose that the upregulation of Aurora-A by estrogen in short-term in vitro cultures is an indirect consequence of estrogen-induced cell proliferation. Nevertheless, Aurora-A inhibitors could be exploited to override the effects of estrogen on breast tumorigenesis and chemoresistance.

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Section: Introductionsupporting

confidence: 53%

Downregulation of Aurora-A overrides estrogen-mediated growth and chemoresistance in breast cancer cells

Lee¹,

Zhu²,

Govindasamy³

et al. 2008

Endocrine Related Cancer

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“…(22) have shown that when a 27.5-mg silastic capsule or 3-mg pellet of E, respectively, is implanted into intact 8-to 9-week-old female August-Copenhagen-Irish (ACI) rats, 100% develop mammary cancers by 6-7 months (21,22) after hormone treatment. This hormone-induced carcinogenesis was shown by Li et al to be preventable if the rats were also provided with the antiestrogen tamoxifen (22). Shull et al (21) also noted that implantation of E capsules failed to induce mammary cancers in ovariectomized (OVX) ACI rats.…”

mentioning

confidence: 99%

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

Blank

Wong

Lakshmanaswamy

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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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...

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“…Estrogen-induced mammary cancer is also accompanied by genomic instability in the form of loss of heterozygosity (Harvell et al, 2000;Li et al, 2002a). TAM has been shown to prevent ACI rat mammary gland tumor formation, and this effect appears to be mediated by the ER (Li et al, 2002b).…”

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confidence: 99%

Protective roles of quinone reductase and tamoxifen against estrogen-induced mammary tumorigenesis

et al. 2006

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We previously reported that antiestrogen-liganded estrogen receptor b (ERb) transcriptionally activates the major detoxifying enzyme quinone reductase (QR) (NAD(P)H:-quinone oxidoreductase). Further studies on the functional role of ERb-mediated upregulation of antioxidative enzymes indicated protective effects against estrogeninduced oxidative DNA damage (ODD). We now report on in vivo and in vitro studies that show that ERbmediated upregulation of QR are involved in the protection against estrogen-induced mammary tumorigenesis. Using the August Copenhagen Irish (ACI) model of estrogen-induced carcinogenesis, we observed that increased ODD and decreased QR expression occur early in the process of estrogen-induced mammary tumorigenesis. Prevention of ACI mammary gland tumorigenesis by tamoxifen was accompanied by decreased ODD and increased QR levels. These correlative findings were supported by our findings that downregulation of QR levels led to increased levels of estrogen quinone metabolites and enhanced transformation potential of 17b-estradiol treated MCF10A non-tumorigenic breast epithelial cells. Concurrent expression of ERb and treatment with 4-hydroxytamoxifen decreased tumorigenic potential of these MCF10A cells. We conclude that upregulation of QR, through induction by tamoxifen, can inhibit estrogen-induced ODD and mammary cell tumorigenesis, representing a possible novel mechanism of tamoxifen prevention against breast cancer.

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Prevention of solely estrogen-induced mammary tumors in female aci rats by tamoxifen: evidence for estrogen receptor mediation

Cited by 60 publications

References 39 publications

Downregulation of Aurora-A overrides estrogen-mediated growth and chemoresistance in breast cancer cells

Downregulation of Aurora-A overrides estrogen-mediated growth and chemoresistance in breast cancer cells

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

Protective roles of quinone reductase and tamoxifen against estrogen-induced mammary tumorigenesis

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