Selective estrogen receptor modulators inhibit growth and progression of premalignant lesions in a mouse model of ductal carcinoma in situ

Namba, Ruria; Young, Lawrence J.T.; Maglione, Jeannie E.; McGoldrick, Erik T.; Liu, Stephenie; Wurz, Gregory T.; DeGregorio, Michael W.; Borowsky, Alexander D.; MacLeod, Carol L.; Cardiff, Robert D.; Gregg, Jeffrey P.

doi:10.1186/bcr1317

Cited by 60 publications

(49 citation statements)

References 32 publications

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“…Overall, the goal of developing a bone specific agent is reasonable, but the key to commercial success will be the prospective demonstration of the prevention of breast and endometrial cancer as beneficial side effects. This remains a possibility based on prevention studies completed in the laboratory [125,126].…”

Section: Metabolic Mimicrymentioning

confidence: 99%

New insights into the metabolism of tamoxifen and its role in the treatment and prevention of breast cancer

2007

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The metabolism of tamoxifen is being redefined in the light of several important pharmacological observations. Recent studies have identified 4-hydroxy N-desmethyl tamoxifen (endoxifen) as an important metabolite of tamoxifen necessary for antitumor actions. The metabolite is formed through the enzymatic product of CYP2D6 which also interacts with specific selective serotonin reuptake inhibitors (SSRIs) used to prevent the hot flashes observed in up to 45% of patients taking tamoxifen. Additionally, the finding that enzyme variants of CYP2D6 do not promote the metabolism of tamoxifen to endoxifen means that significant numbers of women might not receive optimal benefit from tamoxifen treatment. Clearly these are particularly important issues not only for breast cancer treatment but also for selecting premenopausal women, at high risk for breast cancer, as candidates for chemoprevention using tamoxifen.

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Section: Metabolic Mimicrymentioning

confidence: 99%

New insights into the metabolism of tamoxifen and its role in the treatment and prevention of breast cancer

2007

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“…A great majority of DCIS cases express sex-steroid receptors, i.e., estrogen (ER), progesterone (PR), and androgen (AR) receptors (Selim et al 2002, Baqai & Shousha 2003, Moinfar et al 2003, Barnes et al 2005, Rody et al 2005, Kepple et al 2006, which suggest an important role of sex steroids in both DCIS and IDC. Tamoxifen was reported to inhibit the growth of premalignant mammary lesions and the progression to invasive carcinoma in a transplantable mouse model of DCIS (Namba et al 2005). The National Surgical Adjuvant Breast Project (NSABP) P-1 trial demonstrated that tamoxifen significantly reduced the risk of noninvasive breast cancer by 50% (Dunn et al 2005) and results of the NSABP B-24 trial indicated that adjuvant tamoxifen therapy was clinically effective in ER-positive DCIS and reduced the recurrence of non-invasive breast carcinomas by 27% (Cuzick 2003).…”

Section: Introductionmentioning

confidence: 99%

Intratumoral concentration of sex steroids and expression of sex steroid-producing enzymes in ductal carcinoma in situ of human breast

Shibuya¹,

Suzuki²,

Miki³

et al. 2008

Endocrine Related Cancer

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It is well known that sex steroids play important roles in the development of invasive ductal carcinoma (IDC) of the human breast. However, biological significance of sex steroids remains largely unclear in ductal carcinoma in situ (DCIS), regarded as a precursor lesion of IDC, which is partly due to the fact that the intratumoral concentration of sex steroids has not been examined in DCIS. Therefore, in this study, we first examined the intratumoral concentrations of estradiol and 5a-dihydrotestosterone (DHT) using liquid chromatography/electrospray tandem mass spectrometry in DCIS. Intratumoral concentrations of both estradiol and DHT were threefold higher in DCIS than non-neoplastic breast tissues and estrogen-producing enzymes (aromatase, steroid sulfatase, and 17b-hydroxysteroid dehydrogenase type 1 (17bHSD1)), and androgen-producing enzymes (17bHSD5 and 5a-reductase type 1 (5aRed1)) were abundantly expressed in DCIS by real-time PCR and immunohistochemical analyses. The intratumoral concentration of DHT was significantly lower in IDC than DCIS, while the expression of aromatase mRNA in carcinoma cells and intratumoral stromal cells was significantly higher in IDC than those in DCIS. Immunohistochemistry for sex steroid-producing enzymes in DCIS demonstrated that 5aRed1 immunoreactivity was positively correlated with Ki-67 labeling index and histological grade and was also associated with an increased risk of recurrence in patients with DCIS examined. Results of our study suggest that intratumoral concentrations of estradiol and DHT are increased in DCIS, which is possibly due to intratumoral production of these steroids. Therefore, estradiol and DHT may play important roles in the development of DCIS of the human breast.

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“…Indeed, a high expression level of ECT2 protein is associated with neoplastic cell transformation, and amplification of the ECT2 gene was found in esophageal squamous cell carcinoma and carcinogeninduced transformed cells (Clemens et al, 2005;Yen et al, 2005). A genetically engineered mouse model of ductal carcinoma in situ, which histologically resembles human breast cancer, showed that upregulated expression of ECT2 occurs during the early stage of malignant transition from normal mammary gland (Namba et al, 2004). Although many studies suggest that deregulated ECT2 expression is involved in cancer progression, it remains unclear how its transcription is regulated, and whether other oncogenes or tumor suppressor genes are related to its regulation.…”

Section: Introductionmentioning

confidence: 99%

RB silencing compromises the DNA damage-induced G2/M checkpoint and causes deregulated expression of the ECT2 oncogene

et al. 2006

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As alterations in retinoblastoma (RB)/E2F pathway are commonly found in human cancers, the molecular mechanism underlying cell cycle deregulation caused by the mutations in the RB/E2F pathway needs to be investigated extensively. Compared with good understanding of RB/E2F functions in G1-S cell cycle progression, it is not fully understood how an abrogated RB pathway affects the G2-M phase of the cell cycle. Here, we report that disruption of RB accelerated G2-M progression in the presence of DNA damage by elevating the expression of a set of mitotic regulatory genes. We generated RB( þ )-and (À)-matched cells using short hairpin RNA. In the RB(À) cells, the G2/M checkpoint mediated by a DNA-damaging agent was over-ridden. With microarray analysis, we found that the expression of key G2-M regulatory genes was upregulated in RB(À) cells. In particular, we demonstrated that the proto-oncogene ECT2 was directly regulated by E2Fs. Furthermore, suppression of ECT2 expression by small interfering RNA in RB(À) cells resulted in cytokinesis arrest, suggesting that RB(À) cells lack the regulation of E2F-mediated cytokinesis. These results indicate that aberrant ECT2 expression, observed in various human tumors, could be the direct result of RB/E2F pathway deficiency, thereby contributing to cell division in cancers.

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Selective estrogen receptor modulators inhibit growth and progression of premalignant lesions in a mouse model of ductal carcinoma in situ

Cited by 60 publications

References 32 publications

New insights into the metabolism of tamoxifen and its role in the treatment and prevention of breast cancer

New insights into the metabolism of tamoxifen and its role in the treatment and prevention of breast cancer

Intratumoral concentration of sex steroids and expression of sex steroid-producing enzymes in ductal carcinoma in situ of human breast

RB silencing compromises the DNA damage-induced G2/M checkpoint and causes deregulated expression of the ECT2 oncogene

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