Aromatase in Human Breast Carcinoma as a Key Regulator of Intratumoral Sex Steroid Concentrations

Suzuki, Takashi; Miki, Yasuhiro; Akahira, Jun Ichi; Moriya, Takuya; Ohuchi, Noriaki; Sasano, Hironobu

doi:10.1507/endocrj.k07e-053

Cited by 39 publications

(25 citation statements)

References 51 publications

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“…Estrone is subsequently converted to estradiol by 17β-hydroxyteroid dehydrogenase type1 (17β-HSD1). Among the pathways of interatumoral production of estrogens, only aromatase route is irreversible, suggesting that aromatase is a key enzyme in estradiol synthesis [40]. In present paper, our 3 H 2 O assay results demonstrated that triptolide reduced aromatase activity, while aromatase mRNA and protein expression were decreased, as revealed by qRT-PCR and Western blotting.…”

Section: Discussionsupporting

confidence: 60%

Effect of triptolide on estradiol release from cultured rat granulosa cells

Zhang

Liu

et al. 2012

Endocr J

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Section: Discussionsupporting

confidence: 60%

Effect of triptolide on estradiol release from cultured rat granulosa cells

Zhang

Liu

et al. 2012

Endocr J

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“…As aromatase enzyme converts androgens into estrogens, it is thought that if androgens are used in the treatment of ERÀ/AR þ tumors, the therapy should be combined with aromatase inhibitors for maximum benefit. 8,42 The use of AR-related targeted therapy for ER þ breast cancer is somewhat more complicated. The use of androgens may actually stimulate the growth of ER þ cells, 43 as androgen response in ER þ /AR þ cells is different from ER-/AR þ cells.…”

Section: Discussionmentioning

confidence: 99%

Androgen receptor in breast cancer: expression in estrogen receptor-positive tumors and in estrogen receptor-negative tumors with apocrine differentiation

et al. 2010

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Androgens exert growth inhibitory effects on estrogen receptor and progesterone receptor-negative breast cancer cell lines that show androgen receptor expression. These laboratory findings may be translated into inexpensive alternative therapies for hormone receptor-negative invasive breast cancers. Our aim was to systematically evaluate androgen receptor expression by immunohistochemistry in invasive breast cancers. Androgen receptor (clone AR441, Dako) expression was analyzed on 189 well-characterized consecutive invasive breast carcinomas represented with threefold redundancy on tissue microarrays. Androgen receptor expression was semi-quantitated using a histochemical score-like method and a score 410 was considered positive. Of the 189 consecutive invasive breast cancers, 151 (80%) were positive and 38 (20%) were negative for androgen receptor. The majority (95%) of estrogen receptor-positive tumors were also androgen receptor positive. Of the estrogen receptor-negative tumors, androgen receptor reactivity was seen in 3 of 30 (10%) triple-negative cases and in 5/8 (63%) estrogen receptor-negative/progesterone receptor-negative/HER2 þ cases. Six of eight estrogen receptor-negative/androgen receptor-positive cases showed apocrine differentiation. Androgen receptor expression in estrogen receptor-positive cases was associated with smaller tumor size (P ¼ 0.0001), lower Nottingham grade (P ¼ 0.002) and less frequent tumor cell necrosis (P ¼ 0.0001). Androgen receptor expression in estrogen receptor-negative tumors was associated with lower Nottingham grade (P ¼ 0.005) and apocrine differentiation (P ¼ 0.039). In conclusion, most estrogen receptor-positive breast tumors also express androgen receptor. Androgen receptor expression in estrogen receptor-negative/ progesterone receptor-negative/HER2 þ tumors (which commonly show apocrine differentiation) and a subset of triple -negative apocrine tumors suggest that these tumors together comprises the 'molecular apocrine' group described previously. However, these findings should be further confirmed on larger series of triplenegative and estrogen negative/progesterone negative/HER2 þ tumors. Androgen receptor-targeted therapy in estrogen/progesterone receptor-negative tumors may provide an inexpensive alternative to usual high-dose chemotherapy with or without trastuzumab. Keywords: androgen receptor; breast carcinoma; apocrine differentiation Breast cancer represents a diverse group of tumors that vary in clinical behavior and response to therapy. Currently, invasive breast cancer is treated by multi-modality therapy. Approximately 75% of breast cancers are positive for estrogen (ER) and/or progesterone (PR) receptor protein expression. This group of tumors is generally responsive to selective estrogen receptor modulators, 1 with relative resistance seen in a subset of tumors co-expressing HER2. 2 The remaining 20-25% of breast cancers are ER and PR negative and are not amenable to selective estrogen receptor modulators. This hormone receptor-negative group include...

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“…As aromatase enzyme converts androgens into estrogens, it is thought that if androgens are used in the treatment of ERnegative/androgen receptor-positive tumors, the therapy should be combined with aromatase inhibitors for maximum benefit. 44,46 Androgen receptor-targeted therapy in combination with chemotherapy in estrogen/progesterone receptornegative tumors may provide an inexpensive alternative to usual high-dose chemotherapy. The findings of our study may allow a better understanding of the role of androgen receptor in the management of triple-negative and basal-like breast cancer.…”

Section: Discussionmentioning

confidence: 99%

Loss of androgen receptor expression predicts early recurrence in triple-negative and basal-like breast cancer

et al. 2014

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Treatment of triple-negative invasive breast cancers, defined by the absence of estrogen and progesterone receptors and c-erbB2 expression, remains challenging. Androgen receptor, a member of the nuclear receptor superfamily that is involved in signaling pathways regulating cell proliferation, has been implicated in breast tumorigenesis. We immunohistochemically examined the expression of androgen receptor, basal markers (CK14, 34bE12) and EGFR in 699 triple-negative invasive breast cancers in tissue microarrays using the streptavidin-biotin method, and correlated the findings with clinical outcome. Positive androgen receptor expression was defined as staining of 1% or more of tumor cell nuclei. Survival outcomes were estimated with the Kaplan-Meier method and compared between groups with log-rank statistics. Cox proportional hazards models were used to determine the effect of androgen receptor on survival outcomes. Immunohistochemical positivity was observed in 38% of tumors, with the proportion of stained tumor cells ranging from 1 to 95% (mean 29%, median 10%). Androgen receptor expression was inversely associated with histologic grade and mitotic score. CK14, 34bE12 and EGFR confirmed 85% of cases to be basal-like, without significant association of basal-like phenotype with androgen receptor expression. Disease-free survival was significantly better in androgen receptor-positive triple-negative breast cancer, with a trend for improved overall survival. Decreased recurrence likelihood in both triple-negative and basal-like tumors (hazard ratio, 0.704; 95% confidence intervals, 0.498-0.994; P ¼ 0.0464; and hazard ratio, 0.675; 95% confidence intervals, 0.468-0.974; P ¼ 0.0355, respectively) was noted within 5 years of diagnosis but not thereafter. Our study suggests that loss of androgen receptor in triple-negative breast cancers augurs a worse prognosis, including those with basal-like features. More work in elucidating its relationship with mechanisms of progression, as well as trials of targeted treatment for androgen receptor-expressing triple-negative tumors, needs to be performed.

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Aromatase in Human Breast Carcinoma as a Key Regulator of Intratumoral Sex Steroid Concentrations

Cited by 39 publications

References 51 publications

Effect of triptolide on estradiol release from cultured rat granulosa cells

Effect of triptolide on estradiol release from cultured rat granulosa cells

Androgen receptor in breast cancer: expression in estrogen receptor-positive tumors and in estrogen receptor-negative tumors with apocrine differentiation

Loss of androgen receptor expression predicts early recurrence in triple-negative and basal-like breast cancer

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