The presence and impact of estrogen metabolism on the biology of triple-negative breast cancer

McNamara, Keely May; Oguro, Sota; Omata, Fumiya; Kikuchi, Keiko; Guestini, Fouzia; Suzuki, Koyu; Yang, Yang; Abe, Eriko; Higuchi, Hisashi; Brown, Kristy A.; Ishida, Toru; Ohuchi, Noriaki; Sasano, Hironobu

doi:10.1007/s10549-016-4050-2

Cited by 18 publications

(12 citation statements)

References 36 publications

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“…43 However, McNamara et al demonstrated that enzymes known to modulate levels of estrogens were detected in TNBC and were associated with longer disease-free survival, suggesting the presence of, and a potential protective effect of estrogens in TNBC. 44 Current findings speculate the effect of estrogen in TNBC may be mediated by other activating effectors related to ER signaling or other receptors. Consistent with previous studies, 19,20 we observed that high expression of ERRα was associated with aggressive clinicopathologic features in TNBC, including high NG, frequent LNM, and advanced TNM stage, as well as poor survival outcomes.…”

Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 90%

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<p>Estrogen-Related Receptor α (ERRα) and G Protein-Coupled Estrogen Receptor (GPER) Synergistically Indicate Poor Prognosis in Patients with Triple-Negative Breast Cancer</p>

Zhou

et al. 2020

OTT

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The present study aims to demonstrate the correlation between estrogen-related receptor α (ERRα) and G protein-coupled estrogen receptor (GPER) expression and its predictive role in the prognosis of patients with triple-negative breast cancer (TNBC). Methods: A retrospective review of 199 cases of TNBC was conducted to assess the GPER and ERRα expression, and its clinicopathologic and prognostic implications. Subsequently, the effects of ERRα and GPER on cell viability, migration, and invasion induced by estrogen were also investigated in vitro. Results: Compared to TNBCs with ERRα low expression, ERRα-high patients exhibited higher nuclear grade, more frequent lymph nodal metastasis, a higher rate of local recurrence, and distant metastasis. Survival analyses revealed that ERRα-high patients had decreased overall survival (OS), local recurrence-free survival (LRFS), and distant diseasefree survival (DDFS) than ERRα-low patients. The GPER expression level positively correlated with ERRα (R=0.167, P=0.18), and TNBCs with ERRα-low/GPER-low demonstrated the best survival outcomes among groups. In vitro, E2 significantly enhanced cell viability, migration, and invasion in BT-549 and MDA-MB-231 cell lines, which was associated with the increased expression of ERRα. Moreover, the overexpression of ERRα induced by estrogen and G1 (GPER agonist) was reversed by knocking down of GPER and blocking the MAPK signaling with PD98059 in both cell lines. Conclusion: Our findings suggest that ERRα and GPER synergistically predict unfavorable prognosis in TNBCs. Mechanically, GPER mediates the upregulation expression of ERRα induced by estrogen and promotes cell viability, migration, and invasion.

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 90%

<p>Estrogen-Related Receptor α (ERRα) and G Protein-Coupled Estrogen Receptor (GPER) Synergistically Indicate Poor Prognosis in Patients with Triple-Negative Breast Cancer</p>

Zhou

et al. 2020

OTT

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“…This is supported by the fact that HSD17B6 and ERβ are often colocalized in prostate tissue [101]. In triple negative breast cancer, it was shown to be associated with improved outcome, likely by promoting ERβ signaling [102]. …”

Section: Other Hsd17b Enzymesmentioning

confidence: 99%

Estrogen and androgen-converting enzymes 17β-hydroxysteroid dehydrogenase and their involvement in cancer: with a special focus on 17β-hydroxysteroid dehydrogenase type 1, 2, and breast cancer

2017

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Sex steroid hormones such as estrogens and androgens are involved in the development and differentiation of the breast tissue. The activity and concentration of sex steroids is determined by the availability from the circulation, and on local conversion. This conversion is primarily mediated by aromatase, steroid sulfatase, and 17β-hydroxysteroid dehydrogenases. In postmenopausal women, this is the primary source of estrogens in the breast. Up to 70-80% of all breast cancers express the estrogen receptor-α, responsible for promoting the growth of the tissue. Further, 60-80% express the androgen receptor, which has been shown to have tissue protective effects in estrogen receptor positive breast cancer, and a more ambiguous response in estrogen receptor negative breast cancers. In this review, we summarize the function and clinical relevance in cancer for 17β-hydroxysteroid dehydrogenases 1, which facilitates the reduction of estrone to estradiol, dehydroepiandrosterone to androstendiol and dihydrotestosterone to 3α- and 3β-diol as well as 17β-hydroxysteroid dehydrogenases 2 which mediates the oxidation of estradiol to estrone, testosterone to androstenedione and androstendiol to dehydroepiandrosterone. The expression of 17β-hydroxysteroid dehydrogenases 1 and 2 alone and in combination has been shown to predict patient outcome, and inhibition of 17β-hydroxysteroid dehydrogenases 1 has been proposed to be a prime candidate for inhibition in patients who develop aromatase inhibitor resistance or in combination with aromatase inhibitors as a first line treatment. Here we review the status of inhibitors against 17β-hydroxysteroid dehydrogenases 1. In addition, we review the involvement of 17β-hydroxysteroid dehydrogenases 4, 5, 7, and 14 in breast cancer.

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“…Of note, isoflavones have several times higher affinity for ERβ than for ERα, therefore some selectivity in physiological activity among phytoestrogens can be expected [56]. However, some triple negative breast cancers exhibit active ERβ [57]. Some phytoestrogens interfere with steroid hormones biosynthesis; for example, dehydrogenases of 17β-hydroxysteroids, 3β-hydroxysteroids, and aromatase lowering testosterone and estradiol production [55].…”

Section: Enteric Microbes and Phytoestrogensmentioning

confidence: 99%

The Microbiome–Estrogen Connection and Breast Cancer Risk

Parida

Sharma

2019

Cells

152

112

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The microbiome is undoubtedly the second genome of the human body and has diverse roles in health and disease. However, translational progress is limited due to the vastness of the microbiome, which accounts for over 3.3 million genes, whose functions are still unclear. Numerous studies in the past decade have demonstrated how microbiome impacts various organ-specific cancers by altering the energy balance of the body, increasing adiposity, synthesizing genotoxins and small signaling molecules, and priming and regulating immune response and metabolism of indigestible dietary components, xenobiotics, and pharmaceuticals. In relation to breast cancer, one of the most prominent roles of the human microbiome is the regulation of steroid hormone metabolism since endogenous estrogens are the most important risk factor in breast cancer development especially in postmenopausal women. Intestinal microbes encode enzymes capable of deconjugating conjugated estrogen metabolites marked for excretion, pushing them back into the enterohepatic circulation in a biologically active form. In addition, the intestinal microbes also break down otherwise indigestible dietary polyphenols to synthesize estrogen-like compounds or estrogen mimics that exhibit varied estrogenic potency. The present account discusses the potential role of gastrointestinal microbiome in breast cancer development by mediating metabolism of steroid hormones and synthesis of biologically active estrogen mimics.

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The presence and impact of estrogen metabolism on the biology of triple-negative breast cancer

Abstract: Overall this study suggests the presence of, and a potential protective effect of estrogens in TNBC.

Cited by 18 publications

References 36 publications

<p>Estrogen-Related Receptor α (ERRα) and G Protein-Coupled Estrogen Receptor (GPER) Synergistically Indicate Poor Prognosis in Patients with Triple-Negative Breast Cancer</p>

<p>Estrogen-Related Receptor α (ERRα) and G Protein-Coupled Estrogen Receptor (GPER) Synergistically Indicate Poor Prognosis in Patients with Triple-Negative Breast Cancer</p>

Estrogen and androgen-converting enzymes 17β-hydroxysteroid dehydrogenase and their involvement in cancer: with a special focus on 17β-hydroxysteroid dehydrogenase type 1, 2, and breast cancer

The Microbiome–Estrogen Connection and Breast Cancer Risk

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