Targeting the glucocorticoid receptor in breast and prostate cancers

Kach, Jacob; Conzen, Suzanne D.; Szmulewitz, Russell Z.

doi:10.1126/scitranslmed.aac7531

Cited by 64 publications

(63 citation statements)

References 30 publications

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“…Despite there being only nine breast cancer cases in the sample, we observed a negative association with G activity (the average G activity was lower among the women who developed breast cancer compared with those who did not). This is consistent with the observation that GR stimulation decreases the risk of relapse in breast tumors that are ER positive (54) due to cross talk between ER and GR (54,55). We also observed an association between G activity and alcohol intake as reported during the first interview (which for some of the individuals was 4 years before the time of blood draw).…”

Section: Discussionsupporting

confidence: 78%

Association of lifestyle and demographic factors with estrogenic and glucocorticogenic activity in Mexican American women

Fejerman¹,

Sanchez

Thomas

et al. 2016

CARCIN

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Breast cancer risk is higher in US-born than in foreign-born Hispanics/Latinas and also increases with greater length of US residency. It is only partially known what factors contribute to these patterns of risk. To gain new insights, we tested the association between lifestyle and demographic variables and breast cancer status, with measures of estrogenic (E) and glucocorticogenic (G) activity in Mexican American women. We used Chemical-Activated LUciferase gene eXpression assays to measure E and G activity in total plasma from 90 Mexican American women, without a history of breast cancer at the time of recruitment, from the San Francisco Bay Area Breast Cancer Study. We tested associations of nativity, lifestyle and sociodemographic factors with E and G activity using linear regression models. We did not find a statistically significant difference in E or G activity by nativity. However, in multivariable models, E activity was associated with Indigenous American ancestry (19% decrease in E activity per 10% increase in ancestry, P = 0.014) and with length of US residency (28% increase in E activity for every 10 years, P = 0.035). G activity was associated with breast cancer status (women who have developed breast cancer since recruitment into the study had 21% lower G activity than those who have not, P = 0.054) and alcohol intake (drinkers had 25% higher G activity than non-drinkers, P = 0.015). These associations suggest that previously reported breast cancer risk factors such as genetic ancestry and alcohol intake might in part be associated with breast cancer risk through mechanisms linked to the endocrine system.

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Section: Discussionsupporting

confidence: 78%

Association of lifestyle and demographic factors with estrogenic and glucocorticogenic activity in Mexican American women

Fejerman¹,

Sanchez

Thomas

et al. 2016

CARCIN

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“…Increasing evidence supports the proposal that GR plays an important role in ERα positive breast cancer and associates with more favorable clinical outcomes (Abduljabbar et al, 2015; Kach et al, 2015; Karmakar et al, 2013; Pan et al, 2011). Upon ligand induction, GR modulates specific genomic sites that are occupied by ERα, either by direct recognition of EREs or through indirect interaction with other factors (Miranda et al, 2013).…”

Section: Discussionmentioning

confidence: 74%

Glucocorticoid Receptor:MegaTrans Switching Mediates the Repression of an ERα-Regulated Transcriptional Program

Yang

Liu

et al. 2017

Molecular Cell

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Summary The molecular mechanisms underlying the opposing functions of glucocorticoid receptors (GR) and estrogen receptor α (ERα) in breast cancer development remain poorly understood. Here, we report that in breast cancer cells liganded GR represses a large ERα-activated transcriptional program by binding, in trans, to ERα-occupied enhancers. This abolishes effective activation of these enhancers and their cognate target genes, and leads to inhibition of ERα-dependent binding of components of the MegaTrans complex. Consistent with the effects of SUMOylation on other classes of nuclear receptors, dexamethasone (Dex)-induced trans-repression of the estrogen (E2) program appears to depend on GR SUMOylation, which leads to stable trans-recruitment of the GR-NCoR/SMRT-HDAC3 co-repressor complex on these enhancers. Together, these results uncover a mechanism by which competitive recruitment of DNA-binding nuclear receptors/transcription factors in trans to “hot spot” enhancers serves as an effective biological strategy for trans-repression with clear implications for breast cancer and other diseases.

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“…In addition, AR-independent bypass mechanisms of CRPC progression also exist, including activated oncogenic pathways such as PI3K, cMYC (9,10), and increased glucocorticoid receptor alpha (GRα) expression and activity (11,12), hereafter referred to as GR. Research from our group (11) and others (12) examining the role of GR in CRPC reveals that GR activity can indeed promote PC progression following AR blockade, suggesting that GR antagonism is a therapeutic strategy for CRPC (13). …”

Section: Introductionmentioning

confidence: 97%

Selective Glucocorticoid Receptor Modulators (SGRMs) Delay Castrate-Resistant Prostate Cancer Growth

Kach

Long

Selman

et al. 2017

Molecular Cancer Therapeutics

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Increased glucocorticoid receptor (GR) expression and activity following androgen blockade can contribute to castration-resistant prostate cancer (CRPC) progression. Therefore, we hypothesized that GR antagonism will have therapeutic benefit in CRPC. However, the FDA-approved nonselective, steroidal GR antagonist, mifepristone, lacks GR specificity, reducing its therapeutic potential. Here we report that two novel non-steroidal and highly selective GR modulators (SGRMs), CORT118335 and CORT108297, have the ability to block GR activity in prostate cancer (PC) and slow CRPC progression. In contrast to mifepristone, these novel SGRMs did not affect AR signaling, but potently inhibited GR transcriptional activity. Importantly, SGRMs decreased GR-mediated tumor cell viability following AR blockade. In vivo, SGRMs significantly inhibited CRPC progression in high GR-expressing, but not in low GR-expressing xenograft models. Transcriptome analysis following AR blockade and GR activation revealed that these SGRMs block GR-mediated proliferative gene expression pathways. Furthermore, GR-regulated proliferation-associated genes AKAP12, FKBP5, SGK1, CEBPD, and ZBTB16 are inhibited by CORT108297 treatment in vivo. Together, these data suggest that GR-selective non-steroidal SGRMs potently inhibit GR activity and PC growth despite AR pathway inhibition demonstrating the therapeutic potential of SGRMs in GR-expressing CRPC.

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Targeting the glucocorticoid receptor in breast and prostate cancers

Cited by 64 publications

References 30 publications

Association of lifestyle and demographic factors with estrogenic and glucocorticogenic activity in Mexican American women

Association of lifestyle and demographic factors with estrogenic and glucocorticogenic activity in Mexican American women

Glucocorticoid Receptor:MegaTrans Switching Mediates the Repression of an ERα-Regulated Transcriptional Program

Selective Glucocorticoid Receptor Modulators (SGRMs) Delay Castrate-Resistant Prostate Cancer Growth

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