Clinical Importance of Estrogen Receptor-β Evaluation in Breast Cancer Patients Treated With Adjuvant Tamoxifen Therapy

Honma, Naoko; Horii, Rie; Iwase, Takuji; Saji, Shigehira; Younes, Mamoun; Takubo, Kaiyo; Matsuura, M.; Ito, Yoshiaki; Akiyama, Futoshi; Sakamoto, Goi

doi:10.1200/jco.2007.14.2968

Cited by 208 publications

(239 citation statements)

References 37 publications

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“…Given that in MCF-10A cells, tamoxifen increased p21/WAF transcript levels and decreased cyclin A2 expression irrespective of ERb status, we do not have an explanation for this effect. However, the decreased activity of tamoxifen in MCF-7 cells expressing ERb shRNA supports recent publications reporting high ERb expression to be associated with good response to an endocrine therapy [29,30]. Our data also suggest a molecular mechanism which could underly the weakened tamoxifen response, in MCF-7/bKD cells, tamoxifen-triggered induction of p21/WAF expression was significantly weaker.…”

Section: Discussionsupporting

confidence: 68%

Estrogen receptor beta exerts growth-inhibitory effects on human mammary epithelial cells

Treeck

Lattrich

Springwald

et al. 2009

Breast Cancer Res Treat

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Estrogen receptor b (ERb) is widely expressed in mammary epithelium. ERb expression is reported to decline during carcinogenesis of the breast and other tissues. In this study, we examined the consequences of a loss of ERb expression in mammary epithelial cells. We knocked down ERb transcript levels in human mammary epithelial MCF-10A cells and in MCF-7 breast cancer cells by means of stable transfection with a specific shRNA plasmid. ERb knockdown resulted in a significant growth increase of both cell types in a ligand-independent manner. This effect was accompanied by elevated cyclin A2 expression in MCF-10A cells and by decreased expression of growth-inhibitory p21/ WAF and epithelial cell marker cytokeratine 8 in both cell lines. Transfection of ERb shRNA did not alter the absent proliferative estrogen response of MCF-10A cells, but conferred sensitivity to selective estrogen receptor modulator tamoxifen to this cell line. In contrast, ERb knockdown diminished estrogen responsiveness of MCF-7 breast cancer cells and also weakened the effect of tamoxifen on this cell line. These ligand-dependent effects only observed in MCF-7 cells exhibiting a high ERa/b ratio were accompanied by smaller estrogenic repression of p21/WAF expression, an impaired tamoxifen-triggered induction of this gene and by relative downregulation of ERa and cyclin A2 transcript levels. Our data suggest that ERb exerts antiproliferative effects both on MCF-10A and MCF-7 cells in a ligand-and ERa-independent manner by regulation of p21/WAF or cyclin A2 gene expression. Knockdown of ERb in both cell types was sufficient to significantly decrease transcript levels of epithelial cell marker cytokeratin 8. The results of this study support the hypothesis that ERb acts as a tumor suppressor in mammary epithelium.

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Section: Discussionsupporting

confidence: 68%

Estrogen receptor beta exerts growth-inhibitory effects on human mammary epithelial cells

Treeck

Lattrich

Springwald

et al. 2009

Breast Cancer Res Treat

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“…Immunostaining was performed for representative sections of formalin-fixed and paraffin-embedded tissue according to routine methods as described earlier. (27) Estrogen receptor-a, ER-b, and progesterone receptor (PR) was detected by an anti-ER-a mouse monoclonal antibody (clone 1D5; Dako, Glostrup, Denmark), anti-ER-b mouse monoclonal antibody (clone PPG5 ⁄ 10; Dako), and anti-PR mouse monoclonal antibody (clone PgR636; Dako), respectively. The results were assessed by Honma and Saji in a blinded fashion, independently examining the whole slide.…”

mentioning

confidence: 99%

“…Nuclear immunoreactivities for each of the hormone receptors were scored independently by evaluating the percentage of positively-stained cancer cells; the cut-off value was set to 1% for ER-a and PR, and 10% for ER-b, according to conventional criteria or other reports. (27) Discrepancies were resolved by joint review of the slides.…”

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confidence: 99%

Sex steroid hormones in pairs of tumor and serum from breast cancer patients and pathobiological role of androstene‐3β, 17β‐diol

et al. 2011

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Estrogens play an important role in the pathobiology of breast cancer. In postmenopausal women, peripheral synthesis of estrogens from adrenal/ovarian androgens, dehydroepiandrosterone (DHEA) or androstenedione (Adione), by estrogen-metabolizing enzymes is important. Besides estrone (E1) and estradiol (E2), androgen metabolites, such as androstene-3b, 17b-diol (Aenediol) or 5a-androstane-3b, 17b-diol (Aanediol), are known to have estrogenic functions, although they have been studied much less in breast cancer. To precisely elucidate steroid metabolism in breast cancer patients and to identify the pathobiological role of estrogenic androgen metabolites, concentrations of DHEA, Adione, Aenediol, Aanediol, E1, and E2 in pairs of serum and tumor tissue from patients with primary breast cancer were measured by liquid chromatography-tandem mass spectrometry. Cell proliferation assays using Aenediol were performed for four breast cancer cell lines. Serous E2 concentration was extremely low in postmenopausal women; however, a marked increase in tumor tissue was observed in hormone receptor-positive cases. E1 concentration, in contrast, was sustained at a higher level, even in postmenopausal serum, and did not increase in tumor tissue irrespective of the hormone receptor status. Dehydroepiandrosterone was most abundant in all samples, and exhibited a similar pattern as Adione and Aenediol. 5a-Androstane-3b, 17b-diol was undetectable in most samples. Androstene-3b, 17b-diol proliferated estrogen receptor-apositive breast cancer cells in the absence of E2. The intratumoral increase of E2, but not E1, in hormone receptor-positive postmenopausal breast cancer tissue, as well as the proliferative role of Aenediol, was elucidated. (Cancer Sci 2011; 102: 1848-1854 E strogen plays an important role in the pathobiology of breast cancer.(1,2) In postmenopausal women, in whom ovarian function has decreased, the peripheral metabolism of estrogens via estrogen-metabolizing enzymes is important (Fig. 1). (3,4) Peripheral aromatase converts circulating androgens, such as dehydroepiandrosterone (DHEA) and androstenedione (Adione), from the adrenal gland or ovary into estrogens. Steroid sulfatase (STS) hydrolyzes biologically-inactive sulfates of sex steroids, both estrogens and androgens, producing active steroids. 17b-Hydroxysteroid deydrogenase (HSD)-1 converts estrone (E1) into estradiol (E2), the most potent estrogen. In breast cancer tissue, aromatase, (3-7) STS, (8)(9)(10) and HSD-1 (11) have been reported to be abundant. An increase of E2 concentration in cancerous tissue, compared with the serum in postmenopausal women, has been explained by those enzymes localized in the tumor tissue.(4) Estrone sulfotransferase and HSD-2 play opposite roles to STS and HSD-1, respectively (Fig. 1). Aromatase inhibitors (AI) have been standardized for the treatment of postmenopausal patients with hormone receptor-positive breast cancers, (12) in the expectation of decreasing estrogens. Inhibitors of STS (13) or HSD-1 (14,15) have been also devel...

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“…Subsequent to formation of the ER-ligand complex, binding of co-regulatory molecules such as nuclear-receptor co-activator 1 (NCOA1 or SRC1), NCOA2 (TIF2) and NCOA3 (AIB1, TRAM1, RAC3 or ACTR) (Leo & Chen 2000;McKenna et al, 1999) enhance the transcriptional activity of ER accompanied by increased activity of histoneacetyltransferase (HAT) at the promoter site. Other co-regulatory molecules can also partly suppress the transcriptional activity of ER by recruitment of histone-deacetylase complexes such as nuclear-receptor co-repressor 1 (NCOR1) and NCOR2 that influence ER-induced transcription (Chen & Evans, 1995;Horlein et al, 1995). Several of these groups of molecules have been reported to have prominent roles in cancer.…”

Section: Mechanisms Of Estrogen Receptor Induced Cell Proliferationmentioning

confidence: 99%

Endocrine Resistance and Epithelial Mesenchymal Transition in Breast Cancer

Saleh¹,

Luqmani²

2011

Breast Cancer - Focusing Tumor Microenvironment, Stem Cells and Metastasis

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Clinical Importance of Estrogen Receptor-β Evaluation in Breast Cancer Patients Treated With Adjuvant Tamoxifen Therapy

Abstract: Immunohistochemical examination of ER-beta1 in addition to ER-alpha and PR is clinically important in patients with breast cancer treated with tamoxifen monotherapy. Further studies are needed to confirm our findings.

Cited by 208 publications

References 37 publications

Estrogen receptor beta exerts growth-inhibitory effects on human mammary epithelial cells

Estrogen receptor beta exerts growth-inhibitory effects on human mammary epithelial cells

Sex steroid hormones in pairs of tumor and serum from breast cancer patients and pathobiological role of androstene‐3β, 17β‐diol

Endocrine Resistance and Epithelial Mesenchymal Transition in Breast Cancer

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