Deciphering the divergent roles of progestogens in breast cancer

Carroll, Jason S.; Hickey, Theresa E.; Tarulli, Gerard A.; Williams, Michael R.; Tilley, Wayne D.

doi:10.1038/nrc.2016.116

Cited by 100 publications

(94 citation statements)

References 156 publications

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“…T47D-Y cells can also be used to reintroduce single isoform variants or mutants of PR, such as PR-A (T47D-YA cells) and PR-B (T47D-YB cells) or DNA-binding mutant PR (T47D-PRB-mDBD). We have published extensively using these cell line models to define isoform- and phosphorylation-specific PR gene regulation and protein-protein interactions (13, 14, 22–24), and this cell line model remains a powerful and well-established system for studying PR activity (5). …”

Section: Resultsmentioning

confidence: 99%

“…Clinical data have shown increased breast cancer incidence in women taking post-menopausal hormone replacement therapy (HRT) whose combined regimens included estrogen and progestins; this increased risk was not present in women taking estrogen-only HRT (4). Although much debate continues regarding the role for native progesterone in breast cancer development, it is clear that PR, alone or in combination with the estrogen receptor (ER), affects the transcriptional landscape of breast cancer (5–8). …”

Section: Introductionmentioning

confidence: 99%

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Interferon-Stimulated Genes Are Transcriptionally Repressed by PR in Breast Cancer

Walter

Goodman

Singhal

et al. 2017

Molecular Cancer Research

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The progesterone receptor (PR) regulates transcriptional programs that drive proliferation, survival, and stem cell phenotypes. Although the role of native progesterone in the development of breast cancer remains controversial, PR clearly alters the transcriptome in breast tumors. This study identifies a class of genes, interferon-stimulated genes (ISGs), potently downregulated by ligand-activated PR which have not been previously shown to be regulated by PR. Progestin-dependent transcriptional repression of ISGs was observed in breast cancer cell line models and human breast tumors. Ligand-independent regulation of ISGs was also observed, as basal transcript levels were markedly higher in cells with PR knockdown. PR repressed ISG transcription in response to interferon treatment, the canonical mechanism through which these genes are activated. Liganded PR is robustly recruited to enhancer regions of ISGs, and ISG transcriptional repression is dependent upon PR’s ability to bind DNA. In response to PR activation, key regulatory transcription factors that are required for interferon-activated ISG transcription, STAT2 and IRF9, exhibit impaired recruitment to ISG promoter regions, correlating with PR/ligand-dependent ISG transcriptional repression. Interferon activation is a critical early step in nascent tumor recognition and destruction through immune surveillance. As the large majority of breast tumors are PR-positive at the time of diagnosis, PR-dependent downregulation of interferon signaling may be a mechanism through which early PR-positive breast tumors evade the immune system and develop into clinically relevant tumors. Implications: This study highlights a novel transcriptional mechanism through which PR drives breast cancer development and potentially evades the immune system.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Interferon-Stimulated Genes Are Transcriptionally Repressed by PR in Breast Cancer

Walter

Goodman

Singhal

et al. 2017

Molecular Cancer Research

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“…There is currently revived interest in utilizing the natural hormone P4 or new synthetic PR ligands in conjunction with endocrine therapies in ER+ breast cancer (4). This is based on two premises: First, the historical efficacy of synthetic progestins, mostly MPA or its derivatives, in reducing breast tumor growth (reviewed in 14).…”

Section: Discussionmentioning

confidence: 99%

“…Other reservations are based on the surprising observation that synthetic progestins (mostly MPA) in combination with estrogens in postmenopausal hormonal therapies are tumorigenic in the breast (15, 16). However, use of the natural hormone P4 in postmenopausal therapies has not been statistically linked to breast tumor incidence (discussed in 4). At present, a precise delineation of the mechanisms by which P4 is growth-suppressive vs. growth-stimulating, and the resulting phenotype of P4-treated tumors, is still needed to advise appropriate clinical use.…”

Section: Discussionmentioning

confidence: 99%

Breast Cancer Suppression by Progesterone Receptors Is Mediated by Their Modulation of Estrogen Receptors and RNA Polymerase III

et al. 2017

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Greater than 50% of estrogen receptor (ER)-positive breast cancers co-express the progesterone receptor (PR), which can directly and globally modify ER action to attenuate tumor growth. However, whether this attenuation is mediated only through PR-ER interaction remains unknown. To address this question, we assessed tumor growth in ER/PR-positive PDX models of breast cancer where both natural and synthetic progestins were found to antagonize the mitogenic effects of estrogens. Probing the genome-wide mechanisms by which this occurs, we documented that chronic progestin treatment blunted ER-mediated gene expression up to 2-fold at the level of mRNA transcripts. Unexpectedly, <25% of all ER DNA binding events were affected by the same treatment. The PR cistrome displayed a bimodal distribution. In one group, >50% of PR binding sites were co-occupied by ER, with a propensity for both receptors to coordinately gain or lose binding in the presence of progesterone. In the second group, PR but not ER was associated with a large fraction of RNA polymerase III (Pol III)-transcribed tRNA genes, independent of hormone treatment. Notably, we discovered that PR physically associated with the Pol III holoenzyme. Select pre-tRNA and mature tRNA that colocalized with PR and POLR3A at their promoters were relatively decreased in estrogen+progestin treated tumors. Our results illuminate how PR may indirectly impede ER action by reducing the bioavailability of translational molecules needed for tumor growth.

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“…Some 5–10% of breast cancers are caused by genetic factors and unhealthy lifestyle habits (drinking, smoking, obesity and so on) can accelerate the development of breast cancer. Estrogen receptors (ER) and progesterone receptors (PR) are important indicators for detecting breast cancer and the abnormal expression of ER and PR in the body can also lead to breast cancer . Single nucleotide polymorphisms (SNPs) refer to the polymorphisms of nucleic acid sequences caused by the variation of a single nucleotide in the genome.…”

Section: Introductionmentioning

confidence: 99%

Association of polymorphisms in LOC105377871 and CASC16 with breast cancer in the northwest Chinese Han population

Sun

Chen

et al. 2020

The Journal of Gene Medicine

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Background Breast cancer represents the cancer with the highest incidence and mortality among women in the world, and its pathogenesis is complex. Single nucleotide polymorphisms (SNPs) are one of the factors that influence the risk of breast cancer. The present study aimed to investigate the effects of LOC105377871 and CASC16 polymorphisms on the risk of breast cancer in the northwest Chinese Han population. Methods We selected 503 breast cancer patients and 503 healthy controls for the present study. Genotyping was performed using the Agena MassARRAY system (Agenea Bioscience, San Diego, CA, USA) and we evaluated the association between SNPs (rs17530068 and rs4784227) and the risk of breast cancer in four genetic models. Unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Results It was found that the rs17530068 increased the breast cancer risk in log‐additive model (p = 0.047, OR = 1.23, 95% CI = 1.00–1.50). After stratification, the “T” allele of rs4784227 increased the risk of lymph node metastasis in breast cancer patients (allele: p = 0.025, OR = 1.51, 95% CI = 1.05–2.17; codominant model: p = 0.008, OR = 1.99, 95% CI = 1.20–3.31; dominant model: p = 0.008, OR = 1.94, 95% CI = 1.19–3.16; log‐additive model: p = 0.023, OR = 1.52, 95% CI = 1.06–2.19). Conclusions The results of the present study show that, in the northwest Chinese Han population, SNP rs17530068 (LOC105377871) increases the risk of breast cancer and SNP rs4784227 (CASC16) promotes lymph node metastasis in breast cancer patients.

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Deciphering the divergent roles of progestogens in breast cancer

Cited by 100 publications

References 156 publications

Interferon-Stimulated Genes Are Transcriptionally Repressed by PR in Breast Cancer

Interferon-Stimulated Genes Are Transcriptionally Repressed by PR in Breast Cancer

Breast Cancer Suppression by Progesterone Receptors Is Mediated by Their Modulation of Estrogen Receptors and RNA Polymerase III

Association of polymorphisms in LOC105377871 and CASC16 with breast cancer in the northwest Chinese Han population

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