The ERβ4 variant induces transformation of the normal breast mammary epithelial cell line MCF-10A; the ERβ variants ERβ2 and ERβ5 increase aggressiveness of TNBC by regulation of hypoxic signaling

Faria, Michelle; Karami, Samaneh; Granados-Principal, Sergio; Dey, Prasenjit; Verma, Akanksha; Choi, Dong Soon; Elemento, Olivier; Bawa-Khalfe, Tasneem; Chang, Jenny C.; Ström, Anders; Gustafsson, Jan Åke

doi:10.18632/oncotarget.24134

Cited by 15 publications

(15 citation statements)

References 57 publications

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“…Isoforms (splice variants) of ERβ (five known currently, including wild type ERβ1) such as ERβ2 or ERβ5 may negatively affect prognosis [ 35 , 57 , 128 , 129 , 130 ]…”

Section: Figurementioning

confidence: 99%

Estrogens and Progestogens in Triple Negative Breast Cancer: Do They Harm?

Barele

Heemskerk-Gerritsen

Louwers

et al. 2021

Cancers

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Triple-negative breast cancers (TNBC) occur more frequently in younger women and do not express estrogen receptor (ER) nor progesterone receptor (PR), and are therefore often considered hormone-insensitive. Treatment of premenopausal TNBC patients almost always includes chemotherapy, which may lead to premature ovarian insufficiency (POI) and can severely impact quality of life. Hormone replacement therapy (HRT) is contraindicated for patients with a history of hormone-sensitive breast cancer, but the data on safety for TNBC patients is inconclusive, with a few randomized trials showing increased risk-ratios with wide confidence intervals for recurrence after HRT. Here, we review the literature on alternative pathways from the classical ER/PR. We find that for both estrogens and progestogens, potential alternatives exist for exerting their effects on TNBC, ranging from receptor conversion, to alternative receptors capable of binding estrogens, as well as paracrine pathways, such as RANK/RANKL, which can cause progestogens to indirectly stimulate growth and metastasis of TNBC. Finally, HRT may also influence other hormones, such as androgens, and their effects on TNBCs expressing androgen receptors (AR). Concluding, the assumption that TNBC is completely hormone-insensitive is incorrect. However, the direction of the effects of the alternative pathways is not always clear, and will need to be investigated further.

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“…Isoforms (splice variants) of ERβ (five known currently, including wild type ERβ1) such as ERβ2 or ERβ5 may negatively affect prognosis [ 35 , 57 , 128 , 129 , 130 ]…”

Section: Figurementioning

confidence: 99%

Estrogens and Progestogens in Triple Negative Breast Cancer: Do They Harm?

Barele

Heemskerk-Gerritsen

Louwers

et al. 2021

Cancers

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show abstract

“…The different isoforms of ERβ have differing associations with prognosis. For example, ERβ1 tissue expression levels are considered to be lower in aggressive cancers (15)(16)(17)(18)(19). Interestingly, high ERβ1 expression is associated with a higher overall survival in women with breast cancer (20,21).…”

Section: Erβ: Genetic Locus Domain Structure and Isoformsmentioning

confidence: 99%

“…ERβ is unique in that it functions as a tumor suppressor in diverse biologic contexts. ERβ has been implicated in various cancer types, including breast, prostate, lung, glioblastoma, thyroid, and ovarian cancer (15)(16)(17)(18)(19).…”

Section: Erβ Expression and Role In Various Cancer Typesmentioning

confidence: 99%

Estrogen Receptor Beta (ERβ): A Ligand Activated Tumor Suppressor

et al. 2020

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Estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ) belong to a superfamily of nuclear receptors called steroid hormone receptors, which, upon binding ligand, dimerize and translocate to the nucleus where they activate or repress the transcription of a large number of genes, thus modulating critical physiologic processes. ERβ has multiple isoforms that show differing association with prognosis. Expression levels of the full length ERβ1 isoform are often lower in aggressive cancers as compared to normal tissue. High ERβ1 expression is associated with improved overall survival in women with breast cancer. The promise of ERβ activation, as a potential targeted therapy, is based on concurrent activation of multiple tumor suppressor pathways with few side effects compared to chemotherapy. Thus, ERβ is a nuclear receptor with broad-spectrum tumor suppressor activity, which could serve as a potential treatment target in a variety of human cancers including breast cancer. Further development of highly selective agonists that lack ERα agonist activity, will be necessary to fully harness the potential of ERβ.

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“…ERβ4 and 5 isoforms are truncated transcripts unable to bind ligands [25]; both can heterodimerize with ERβ1 and enhance its transactivation in a ligand-dependent manner [27]. ERβ4 can transform normal mammary epithelial cells, ERβ5 and ERβ2 sustain the tumor growth in a hypoxic environment and increase the c-Myc expression that correlates to bad prognosis in BC [34].…”

Section: Erβ: Structure and Functionmentioning

confidence: 99%

ERβ in Triple-Negative Breast Cancer: Emerging Concepts and Therapeutic Possibilities

et al. 2021

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Despite the improvements in diagnostic and therapeutic approaches, breast cancer still remains one of the world’s leading causes of death among women. Particularly, triple negative breast cancer (TNBC) is characterized by aggressiveness, metastatic spreading, drug resistance and a very high percentage of death in patients. Nowadays, identification of new targets in TNBC appears very compelling. TNBC are considered negative for the estrogen receptor alpha (ERα) expression. Nevertheless, they often express ERβ and its variants. As such, this TNBC subtype still responds to estrogens. While the ERβ1 variant seems to act as a tumor-suppressor, the two variants ERβ2 and 5 exhibit pro-oncogenic activities in TNBC. Thus, ERβ1 activation might be used to limit the growth and spreading as well as to increase the drug sensitivity of TNBC. In contrast, the pro-oncogenic properties of ERβ2 and ERβ5 suggest the possible development and clinical use of specific antagonists in TNBC treatment. Furthermore, the role of ERβ might be regarded in the context of the androgen receptor (AR) expression, which represents another key marker in TNBC. The relationship between AR and ERβ as well as the ability to modulate the receptor-mediated effects through agonists/antagonists represent a challenge to develop more appropriate therapies in clinical management of TNBC patients. In this review, we will discuss the most recent data in the field. Therapeutic implications of these findings are also presented in the light of the discovery of specific ERβ modulators.

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The ERβ4 variant induces transformation of the normal breast mammary epithelial cell line MCF-10A; the ERβ variants ERβ2 and ERβ5 increase aggressiveness of TNBC by regulation of hypoxic signaling

Cited by 15 publications

References 57 publications

Estrogens and Progestogens in Triple Negative Breast Cancer: Do They Harm?

Estrogens and Progestogens in Triple Negative Breast Cancer: Do They Harm?

Estrogen Receptor Beta (ERβ): A Ligand Activated Tumor Suppressor

ERβ in Triple-Negative Breast Cancer: Emerging Concepts and Therapeutic Possibilities

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