C/EBPα mediates the growth inhibitory effect of progestins on breast cancer cells

Nacht, A. Silvina; Ferrari, Roberto; Zaurín, Roser; Scabia, Valentina; Carbonell-Caballero, José; Dily, François Le; Leopoldi, Alexandra; Brisken, Cathrin; Beato, Miguel; Vicent, Guillermo P.

doi:10.15252/embj.2018101426

Cited by 16 publications

(20 citation statements)

References 87 publications

(126 reference statements)

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“…The AR, like most nuclear receptors, binds to thousands of chromosomal sites but only regulates hundreds of genes 49,60,61 . The majority of AR-regulated gene promoters therefore physically interact with multiple ARBS 7 .…”

Section: Discussionmentioning

confidence: 99%

Functional mapping of androgen receptor enhancer activity

Huang

Lingadahalli

Morova

et al. 2020

Preprint

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Androgen receptor (AR) is critical to the initiation, growth and progression of almost all prostate cancers. Once activated, the AR binds to cis-regulatory enhancer elements on DNA that drive gene expression. Yet, there are 10-100x more binding sites than differentially expressed genes. It still remains unclear how individual sites contribute to AR-mediated transcription. While descriptive functional genomic approaches broadly correlate with enhancer activity, they do not provide the locus-specific resolution needed to delineate the underlying regulatory logic of AR- mediated transcription. Therefore, we functionally tested all commonly occuring clinical AR binding sites with Self-Transcribing Active Regulatory Regions sequencing (STARRseq) to generate the first map of intrinsic AR enhancer activity. This approach is not significantly affected by endogenous chromatin modifications and measures the potential enhancer activity at each cis- regulatory element. Interestingly we found that only 7% of AR binding sites displayed increased enhancer activity upon hormonal stimulation. Instead, the vast majority of AR binding sites were either inactive (81%) or constitutively active enhancers (11%). These annotations strongly correlated with enhancer-associated features in both cell line and clinical prostate cancer. With these validated annotations we next investigated the effect of each enhancer class on transcription and found that AR-driven inducible enhancers frequently interacted with promoters, forming central chromosomal loops critical for gene transcription. We demonstrated that these inducible enhancers act as regulatory hubs that increase contacts with both other AR binding sites and gene promoters. This functional map was used to identify a somatic mutation that significantly reduces the expression of a commonly mutated AR-regulated tumour suppressor. Together, our data reveal a complex interplay between different AR binding sites that work in a highly coordinated manner to drive gene transcription.

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Section: Discussionmentioning

confidence: 99%

Functional mapping of androgen receptor enhancer activity

Huang

Lingadahalli

Morova

et al. 2020

Preprint

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“…Transcriptional regulation in early stage of lactation and in later involution process [46] Tumor suppressor [46][47][48] c/EBPβ Promotes adipogenesis. Transcription factor at pre-adipogenesis.…”

Section: Transcriptional Regulation Of Adipose Tissuementioning

confidence: 99%

“…After binding to the adipogenic enhancer sites on PPARγ and C/EBPα, it assists other adipogenic transcription factors such as the glucocorticoid receptor, STAT5A and RXR 9 to form adipogenic enhancers [49]. PPARγ and C/EBPα both play a role in the terminal differentiation of adipogenesis and are both considered tumor suppressors [45][46][47][48]95]. However, evidence suggests that PPARγ does not initiate tumor formation in normal breasts whereas in a tumor environment, the expression of PPARγ results in tumor progression signaling [45].…”

Section: Ndmentioning

confidence: 99%

The Importance of Breast Adipose Tissue in Breast Cancer

Kothari

Diorio

Durocher

2020

IJMS

112

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Adipose tissue is a complex endocrine organ, with a role in obesity and cancer. Adipose tissue is generally linked to excessive body fat, and it is well known that the female breast is rich in adipose tissue. Hence, one can wonder: what is the role of adipose tissue in the breast and why is it required? Adipose tissue as an organ consists of adipocytes, an extracellular matrix (ECM) and immune cells, with a significant role in the dynamics of breast changes throughout the life span of a female breast from puberty, pregnancy, lactation and involution. In this review, we will discuss the importance of breast adipose tissue in breast development and its involvement in breast changes happening during pregnancy, lactation and involution. We will focus on understanding the biology of breast adipose tissue, with an overview on its involvement in the various steps of breast cancer development and progression. The interaction between the breast adipose tissue surrounding cancer cells and vice-versa modifies the tumor microenvironment in favor of cancer. Understanding this mutual interaction and the role of breast adipose tissue in the tumor microenvironment could potentially raise the possibility of overcoming breast adipose tissue mediated resistance to therapies and finding novel candidates to target breast cancer.

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“…Although administration of PR agonist MPA to mice promotes the formation of mammary tumors initiated by DMBA [31], it exerts a biphasic response in cell lines, such as a rapid proliferation burst followed by a sustained growth arrest [32][33][34]. More recently, several articles clearly showed that in addition to proliferative action, under certain circumstances, progesterone has also an anti-proliferative action in cellulo and in vivo [22,34,35]. Interestingly, although ERα-36 has no striking effect on cell growth, we found that its depletion abolished the inhibitory effect of progesterone on FBS-and E2-dependent cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

“…The p value determined by comparing each ERα-36 KO clone to the corresponding condition in WT cells using Student's t test was not significant the RNA polymerase III, regulating tRNA transcription affecting gene sets at the translational level [35]. More recently, Vicent's team showed that progesterone negatively regulates cell proliferation via a functional crosstalk with the transcription factor C/EBPα [34]. Interestingly, we found that the progesterone-induced C/EBPα expression was dependent on ERα-36.…”

Section: Discussionmentioning

confidence: 99%

ERα-36 regulates progesterone receptor activity in breast cancer

et al. 2020

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Background: Alterations in estrogen and progesterone signaling, via their respective receptors, estrogen receptor alpha (ERα) and progesterone receptor (PR), respectively, are largely involved in the development of breast cancer (BC). The recent identification of ERα-36, a splice variant of ERα, has uncovered a new facet of this pathology. Although ERα-36 expression is associated with poor prognosis, metastasis development, and resistance to treatment, its predictive value has so far not been associated with a BC subtype and its mechanisms of action remain understudied. Methods: To study ERα-36 expression in BC specimens, we performed immunochemical experiments. Next, the role of ERα-36 in progesterone signaling was investigated by generating KO clones using the CRISPR/CAS9 technology. PR signaling was also assessed by proximity ligation assay, Western blotting, RT-QPCR, and ChIP experiments. Finally, proliferation assays were performed with the IncuCyte technology and migration experiments using scratch assays. Results: Here, we demonstrate that ERα-36 expression at the plasma membrane is correlated with a reduced diseasefree survival in a cohort of 160 BC patients, particularly in PR-positive tumors, suggesting a crosstalk between ERα-36 and PR. Indeed, we show that ERα-36 interacts constitutively with PR in the nucleus of tumor cells. Moreover, it regulates PR expression and phosphorylation on key residues, impacting the biological effects of progesterone. Conclusions: ERα-36 is thus a regulator of PR signaling, interfering with its transcriptional activity and progesteroneinduced anti-proliferative effects as well as migratory capacity. Hence, ERα-36 may constitute a new prognostic marker as well as a potential target in PR-positive BC.

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C/EBPα mediates the growth inhibitory effect of progestins on breast cancer cells

Cited by 16 publications

References 87 publications

Functional mapping of androgen receptor enhancer activity

Functional mapping of androgen receptor enhancer activity

The Importance of Breast Adipose Tissue in Breast Cancer

ERα-36 regulates progesterone receptor activity in breast cancer

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