Nuclear Hormone Receptor Signaling for Cancer Research

Nuclear hormone receptors bind sequence-specific promoter elements on target genes, while also modulating the expression of genes. Altered expression patterns in these receptors have been linked to several different types of cancers.

Limitation of Androgen Ablation Therapy

Both normal cells and cancer prostate cells require androgen to proliferate. The function of androgens is mediated by the androgen receptor (AR), part of the steroid hormone superfamily of nuclear receptors. The AR is a ligand-dependant transcription factor, which binds to specific androgen response elements (ARE) on the promoter regions of target genes. This can induce or repress gene transcription. Even after androgen ablation therapy, androgen receptor signaling is the central regulator of tumor cells.

Because of this, therapeutic development for castrate-resistance prostate cancer has become focused on AR signaling axis. AR activation promotes the growth and differentiation of prostate cancer cells. AR signaling has also been linked to breast cancer. Additionally, the transcriptional activity of androgen receptors can be altered by growth factors, triggering the proliferation of prostate cancer cells without the presence of androgens.

Compounds to Study Androgen Receptors

There is a wide range of compounds enabling the study of the role of androgen receptors in cancer cases, including classic agonists, antagonists and modulators, and compounds that control hormone release levels. Important compounds in prostate cancer research include the endogenous AR agonist testosterone, the potent and selective androgen receptor modulator (SARM) TFM-4AS-1, and the serum- and glucocorticoid-regulated kinase 1 (SGK1) inhibitor GSK 650394, the latter of which has been proved to suppress androgen-stimulated growth of a human prostate carcinoma cell line.

Key Estrogen Receptor Compounds

Estrogen plays an important role in the growth of breast cancer cells, and estrogenic signal transduction pathways regularly become dysregulated in breast cancer cases. Breast cancer is classified into ERα positive (ER+) or ER-negative (ER–). Important estrogen receptor (ER) compounds include the ER antagonist/partial agonist tamoxifen and its metabolite (Z)-4-hydroxytamoxifen, which is used as a chemotherapeutic agent; the high-affinity ER antagonist ICI 182,780 and the potent selective estrogen receptor modulators (SERM) bazedoxifene and raloxifene. Moreover, the Tocris range of ER compounds includes the highly potent and selective ERβ agonist DPN, with 70-fold selectivity over ERα, and the selective ERβ antagonist PHTPP, which displays 36-fold selectivity over ERα.


While ER+ breast tumors are often very responsive to antiestrogen therapies, ER tumors are not as responsive. These particular tumors are aggressive and carry a poor prognosis. As ER tumors account for ~30% of all breast cancer cases, there is a clear and crucial need for other practical targets. It has stated that GPR30 is expressed in ER tumors and is being studied to determine its antitumor effects. GPR30 activation brings on MAPK and PI 3-K signaling pathways and can modulate cell growth in cancers that respond to hormones. As a result, it is hypothesized that GPR30 could modulate the estrogen response in ER tumors.

However, current studies have produced conflicting results, with some suggesting that GPR30 activation facilitates the proliferation of tumor cells, while others have said that GPR30 activation inhibits proliferation. As such, more studies are needed to definitively say whether GPR30 activation facilitates or inhibits proliferation.

In addition to their roles as ER ligands, ICI 182,780 and tamoxifen also act as high-affinity agonists for GPR30. However, their lack of selectivity for GPR30 limits their use in clarifying the function of GPR30. G-1 is a potent and selective GPR30 receptor agonist, which displays no activity at ERα or ERβ (at concentrations up to 10 μM) and therefore may be a useful tool for selectively investigating GPR30. G-1 has been shown to impede the migration of breast cancer cells in vitro and block cell cycle progression at the G1 phase. The high affinity and selective GPR30 receptor antagonist G-15, also displays no affinity for ERα and ERβ (at concentrations up to 10 μM) and has been shown to antagonize the effects of estrogen in vivo.

Mechanisms behind Estrogen-Related Breast Cancer

The mechanisms behind the estrogen-related development of breast cancer are also under investigation for cancer therapies. For example, aromatase is a CYP450 enzyme involved in estrogen biosynthesis. As estrogen is needed for breast and ovarian cancers to grow and develop, inhibitors of aromatase work against cancer development by bringing down levels of estrogen. For example, letrozole, a potent, reversible, non-steroidal aromatase inhibitor has shown antitumor effects in several animal models. It has also been proved to and suppresses the proliferation of breast cancer cells brought on by endogenous aromatase.

Aryl hydrocarbon receptors (AHRs) are cytosolic transcription factors that trigger alter gene expression upon ligand binding. AHR signaling has been linked with the growth of malignancies, and studies have shown that tumor-derived ligands bind AHRs and reduce antitumor immune responses. The high-affinity endogenous AHR agonist ITE is one of several compounds that display antitumor activity. ITE decreases the levels of the master pluripotency factor Oct4, inducing stem-like cancer cell differentiation in glioblastoma cells. ITE is also able to suppress tumor growth in glioblastoma xenografts in mice models.

Many signaling mechanisms can be dysregulated in cancer cells. By targeting critical receptors and signaling molecules using selective pathway inhibitors, those researching cancer can investigate one of the major hallmarks of cancer and its impact on the development of tumors and their progression.

About Tocris Bioscience

Tocris Bioscience is your trusted supplier of high-performance life science reagents, including receptor agonists & antagonists, enzyme inhibitors, ion channel modulators, fluorescent probes & dyes, and compound libraries. Our catalog consists of over 4,500 research tools, covering over 400 protein targets enabling you to investigate and modulate the activity of numerous signaling pathways and physiological processes.

We have been working with scientists for over 30 years to provide the life science community with research standards, as well as novel and innovative research tools. We understand the need for researchers to trust their research reagents, which is why we are committed to supplying our customers with the highest quality products available, so you can publish with confidence.

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Last updated: Jun 12, 2020 at 9:01 AM


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