Signaling pathways and steroid receptors modulating estrogen receptor α function in breast cancer

Siersbæk, Rasmus; Kumar, Sanjeev; Carroll, Jason S.

doi:10.1101/gad.316646.118

Cited by 117 publications

(96 citation statements)

References 145 publications

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“…Estrogen, a female hormone, promotes the development of the normal mammary duct and the proliferation of breast cancer (reviews Deroo and Korach, 2006;Heldring et al, 2007;Liang and Shang, 2013;Manavathi et al, 2013). There are a number of studies on the function of estrogen in breast cancer (reviews Burns and Korach, 2012;Deroo and Korach, 2006;Liang and Shang, 2013;Manavathi et al, 2013;Siersbaek et al, 2018). Although estrogen is thought to be involved in breast tumorigenesis in epidemiologic studies (Dall Figure 1.…”

Section: Introductionmentioning

confidence: 99%

Estrogen Induces Mammary Ductal Dysplasia via the Upregulation of Myc Expression in a DNA-Repair-Deficient Condition

et al. 2020

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Mammary ductal dysplasia is a phenotype observed in precancerous lesions and early-stage breast cancer. However, the mechanism of dysplasia formation remains elusive. Here we show, by establishing a novel dysplasia model system, that estrogen, a female hormone, has the potential to cause mammary ductal dysplasia. We injected estradiol (E2), the most active form of estrogen, daily into scid mice with a defect in non-homologous end joining repair and observed dysplasia formation with cell proliferation at day 30. The protooncogene Myc is a downstream target of estrogen signaling, and we found that its expression is augmented in mammary epithelial cells in this dysplasia model. Treatment with a Myc inhibitor reduced E2-induced dysplasia formation. Moreover, we found that isoflavones inhibited E2-induced dysplasia formation. Our dysplasia model system provides insights into the mechanistic understanding of breast tumorigenesis and the development of breast cancer prevention.

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Section: Introductionmentioning

confidence: 99%

Estrogen Induces Mammary Ductal Dysplasia via the Upregulation of Myc Expression in a DNA-Repair-Deficient Condition

et al. 2020

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“…tamoxifen) or ER downregulators (e.g. fulvestrant) constitute the first-line treatment for ER + BC (reviewed in (2)).…”

Section: Introductionmentioning

confidence: 99%

Estrogen deprivation triggers an immunosuppressive phenotype in breast cancer cells

Hühn

Martí‐Rodrigo

Mourón³

et al. 2019

Preprint

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Estrogen receptor (ER)-positive breast tumors are routinely treated with estrogen-depriving therapies. Despite their effectiveness, patients often progress into a more aggressive form of the disease. Through a chemical screen oriented to identify chemicals capable of inducing the expression of the immune-checkpoint ligand PD-L1, we found antiestrogens as hits. Subsequent validations confirmed that estrogen deprivation or ERa depletion induces PD-L1 expression in ER-positive breast cancer cells, both in vitro and in vivo. Likewise, PD-L1 expression is increased in metastasis arising from breast cancer patients receiving adjuvant hormonal therapy for their local disease. Transcriptome analyses indicate that estrogen deprivation triggers a broad immunosuppressive program, not restricted to PD-L1. Accordingly, estrogen deprived MCF7 cells are resistant to T-cell mediated cell killing, in a manner that can be reverted by estradiol. Our study reveals that while antiestrogen therapies effectively limit tumor growth in ER-positive breast cancers, they also trigger a transcriptional program that favors immune evasion.

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“…Oestrogen is known to interact with the MAPK pathway, also in breast cancer [Rebbeck et al, 2009;Yu et al, 2012;Siersbaek et al, 2018]. For example, genistein, an oestrogenic isoflavone found in soybeans, rapidly and significantly activates p38 and inactivates ERK1/ERK2 [Frey and Singletary, 2003], and even low doses of genistein can induce an ERα mediated response via MAPK [Yu et al, 2016].…”

mentioning

confidence: 99%

Transcriptomic Analysis of MAP3K1 and MAP3K4 in the Developing Marsupial Gonad

Paranjpe¹,

Yu²,

Frankenberg³

et al. 2019

Sex Dev

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crease in the expression of male-determining genes SOX9 and AMH and increase in the female marker FOXL2 in oestrogen-treated male gonads. Only MAP3K1 expression increased in male gonads in response to oestrogen while other MAPK genes remained unaffected. This study suggests that MAP3K1 can be influenced by exogenous oestrogens during gonadal differentiation in this marsupial. © 2020 S. Karger AG, Basel Disorders of sex development are common birth abnormalities in humans that affect 1.7% of live births [Fausto-Sterling, 2000]. These disorders frequently lead to infertility or gonadal cancers and have profound effects on the individuals, their families, and society. Despite the progress made in identifying genes controlling sexual differentiation of the gonad, the aetiology of disorders of sex development in most cases remains unknown, indicating there are other genetic or environmental factors at play in gonadal differentiation. Testis determination in man, mouse, and marsupial is under primary genetic control of Abstract MAPKs affect gonadal differentiation in mice and humans, but whether this applies to all mammals is as yet unknown. Thus, we investigated MAPK expression during gonadal differentiation and after treatment with oestrogen in a distantly related mammal, the marsupial tammar wallaby, using our model of oestrogen-induced gonadal sex reversal. Highthroughput RNA-sequencing was carried out on gonads collected from developing tammar 2 days before birth to 8 days after birth to characterise MAPK and key sexual differentiation markers. Day 25 foetal testes were cultured for 120 h in control medium or medium supplemented with exogenous oestrogen and processed for RNA-seq to identify changes in gene expression in response to oestrogen. MAPK pathway genes in the tammar were highly conserved at the sequence and amino acid level with those of mice and humans. Marsupial MAP3K1 and MAP3K4 clustered together in a separate branch from eutherian mammals. There was a marked de-

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Signaling pathways and steroid receptors modulating estrogen receptor α function in breast cancer

Cited by 117 publications

References 145 publications

Estrogen Induces Mammary Ductal Dysplasia via the Upregulation of Myc Expression in a DNA-Repair-Deficient Condition

Estrogen Induces Mammary Ductal Dysplasia via the Upregulation of Myc Expression in a DNA-Repair-Deficient Condition

Estrogen deprivation triggers an immunosuppressive phenotype in breast cancer cells

Transcriptomic Analysis of MAP3K1 and MAP3K4 in the Developing Marsupial Gonad

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