Estrogen receptor-positive (ER+) breast cancer treatment: Are multi-target compounds the next promising approach?

Almeida, Cristina Ferreira; Oliveira, Ana; Ramos, María J.; Fernandes, Pedro A.; Teixeira, Natércia; Amaral, Cristina

doi:10.1016/j.bcp.2020.113989

Cited by 38 publications

(17 citation statements)

References 175 publications

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“…Antiestrogen therapy involves small molecules that induce conformational changes in ERα that prevent E2 binding, cause ERα degradation, or block E2 synthesis by inhibiting the activity of aromatase. Based on these mechanisms of action, anti-estrogen therapies can be broadly divided into three groups: selective estrogen receptor modulators (SERMs), selective estrogen receptor down regulators/degraders (SERDs), and aromatase inhibitors (AIs) [54,55].…”

Section: Anti-estrogen Therapies For Breast Cancermentioning

confidence: 99%

Nexus between PI3K/AKT and Estrogen Receptor Signaling in Breast Cancer

Khatpe

Adebayo

Herodotou

et al. 2021

Cancers

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Signaling from estrogen receptor alpha (ERα) and its ligand estradiol (E2) is critical for growth of ≈70% of breast cancers. Therefore, several drugs that inhibit ERα functions have been in clinical use for decades and new classes of anti-estrogens are continuously being developed. Although a significant number of ERα+ breast cancers respond to anti-estrogen therapy, ≈30% of these breast cancers recur, sometimes even after 20 years of initial diagnosis. Mechanism of resistance to anti-estrogens is one of the intensely studied disciplines in breast cancer. Several mechanisms have been proposed including mutations in ESR1, crosstalk between growth factor and ERα signaling, and interplay between cell cycle machinery and ERα signaling. ESR1 mutations as well as crosstalk with other signaling networks lead to ligand independent activation of ERα thus rendering anti-estrogens ineffective, particularly when treatment involved anti-estrogens that do not degrade ERα. As a result of these studies, several therapies that combine anti-estrogens that degrade ERα with PI3K/AKT/mTOR inhibitors targeting growth factor signaling or CDK4/6 inhibitors targeting cell cycle machinery are used clinically to treat recurrent ERα+ breast cancers. In this review, we discuss the nexus between ERα-PI3K/AKT/mTOR pathways and how understanding of this nexus has helped to develop combination therapies.

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Section: Anti-estrogen Therapies For Breast Cancermentioning

confidence: 99%

Nexus between PI3K/AKT and Estrogen Receptor Signaling in Breast Cancer

Khatpe

Adebayo

Herodotou

et al. 2021

Cancers

View full text Add to dashboard Cite

show abstract

“…Aromatase inhibitors block the enzyme aromatase that catalyzes the conversion of androgens into oestrogens, the primary source of endogenous oestrogens in postmenopausal women. This is relevant since anti-estrogen therapy aims to prevent access of the tumour to oestrogen and has been considered the standard of care in ER+ tumours [127].…”

Section: Dietary (Poly)phenols and Clinical Studies In Breast Cancer mentioning

confidence: 99%

Dietary Phenolics against Breast Cancer. A Critical Evidence-Based Review and Future Perspectives

Ávila‐Gálvez

Giménez‐Bastida

Espı́n

et al. 2020

IJMS

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Breast cancer (BC) is the most common malignancy and the leading cause of cancer-related death in adult women worldwide. Over 85% of BC cases are non-hereditary, caused by modifiable extrinsic factors related to lifestyle, including dietary habits, which play a crucial role in cancer prevention. Although many epidemiological and observational studies have inversely correlated the fruit and vegetable consumption with the BC incidence, the involvement of their phenolic content in this correlation remains contradictory. During decades, wrong approaches that did not consider the bioavailability, metabolism, and breast tissue distribution of dietary phenolics persist behind the large currently existing gap between preclinical and clinical research. In the present review, we provide comprehensive preclinical and clinical evidence according to physiologically relevant in vitro and in vivo studies. Some dietary phenolics such as resveratrol (RSV), quercetin, isoflavones, epigallocatechin gallate (EGCG), lignans, and curcumin are gaining attention for their chemopreventive properties in preclinical research. However, the clinical evidence of dietary phenolics as BC chemopreventive compounds is still inconclusive. Therefore, the only way to validate promising preclinical results is to conduct clinical trials in BC patients. In this regard, future perspectives on dietary phenolics and BC research are also critically discussed.

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“…Anti-estrogen therapy involves small molecules that induce conformational changes in ER that prevent E2 binding, cause ER degradation, or block E2 synthesis by inhibiting the activity of aromatase. Based on these mechanisms of action, anti-estrogen therapies can be broadly divided into three groups; selective estrogen receptor modulators (SERMs), selective estrogen receptor down regulators/degraders (SERDs), and aromatase inhibitors (AIs) [27,28].…”

Section: Biology Of Ersmentioning

confidence: 99%

Nexus Between PI3K/AKT and Estrogen Receptor Signaling in Breast Cancer

Khatpe

Adebayo

Herodotou

et al. 2020

Preprint

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Signaling from estrogen receptor alpha (ER) and its ligand estradiol (E2) is critical for growth of ~70% of breast cancers. Therefore, several drugs that inhibit ER functions are in clinical use for decades and new classes of anti-estrogens are continuously being developed. Although a significant number of ER+ breast cancers respond to anti-estrogen therapy, ~30% of these breast cancers recur, sometimes even after 20 years of initial diagnosis. Mechanism of resistance to anti-estrogens is one of the intensely studied disciplines in breast cancer. Several mechanisms have been proposed including mutations in ESR1, crosstalk between growth factor and ER signaling, and interplay between cell cycle machinery and ER signaling. ESR1 mutations as well as crosstalk with other signaling networks lead to ligand independent activation of ER thus rendering anti-estrogens ineffective, particularly when treatment involved anti-estrogens that do not degrade ERa. As a result of these studies, several therapies that combine anti-estrogens that degrade ER with PI3K/AKT/mTOR inhibitors targeting growth factor signaling or CDK4/6 inhibitors targeting cell cycle machinery are used clinically to treat recurrent ER+ breast cancers. In this review, we discuss nexus between ER-PI3K/AKT/mTOR pathways and how understanding of this nexus has helped to develop combination therapies.

show abstract

Estrogen receptor-positive (ER+) breast cancer treatment: Are multi-target compounds the next promising approach?

Cited by 38 publications

References 175 publications

Nexus between PI3K/AKT and Estrogen Receptor Signaling in Breast Cancer

Nexus between PI3K/AKT and Estrogen Receptor Signaling in Breast Cancer

Dietary Phenolics against Breast Cancer. A Critical Evidence-Based Review and Future Perspectives

Nexus Between PI3K/AKT and Estrogen Receptor Signaling in Breast Cancer

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