A link between GRK4, hypertension, and breast cancer

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The enzyme GRK4 (G protein-coupled receptor kinase 4) is implicated in the development of both hypertension (high blood pressure) and breast cancer. Dr Wei Yue and colleagues at the University of Virginia, USA, investigate the relationship between GRK4 and these two diseases. Identification of hypertension-associated GRK4 genetic variations in breast cancer cells suggests an intrinsic link. Through careful experimental design, Yue’s latest study reveals a role for GRK4 as an independent promoter of breast cancer cell growth and spread. Her research highlights GRK4 as a potential therapeutic target for breast cancer, particularly for individuals with hypertension.
Globally, both hypertension (high blood pressure) and breast cancer are common diseases in women, increasing in prevalence with age. It is estimated that one in three women have hypertension, while one in eight will develop breast cancer. Studies reveal an association between hypertension and breast cancer risk, showing that breast cancer is around 15% more prevalent in women with hypertension, even after adjusting for common risk factors. The link between these two diseases is particularly strong in postmenopausal women. The enzyme, G protein-coupled receptor kinase 4 (GRK4), implicated in the pathogenesis of hypertension, is also linked to breast cancer. In a recent study published in Breast Cancer: Basic and Clinical Research, Dr Wei Yue and colleagues at the University of Virginia, USA, provide mechanistic insight into the role of GRK4 in these diseases.

GRK4 in hypertension

There are seven G protein-coupled receptor kinases (GRKs). GRK4 is expressed in the kidney, brain, and testes and has four variants, or isoforms, which differ slightly in genetic sequence. Within the kidney, GRK4 is an important regulator of sodium excretion.

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Hypertension is caused by complex interactions of genetic and environmental factors. High salt consumption is considered the most important environmental risk factor of hypertension. The kidneys are essential for regulating blood pressure, by regulating the volume and composition of bodily fluids. This control is mediated by the dopaminergic receptor: D1R.

One way the kidneys control blood pressure is by regulating sodium excretion, which is increased in response to high salt intake. Thus, the function of D1R within the kidneys is pivotal for blood pressure regulation. To function, D1R is linked to G-protein. When D1R signalling and thus sodium excretion is no longer required (eg, in periods of low salt intake), GRK4 stops this signalling through phosphorylation of D1R. However, any abnormal increase in GRK4 activation or activity alters D1R function, which affects sodium excretion. This leads to hypertension. Specifically, three variants of GRK4 are known to increase GRK4 activity.

“The enzyme GRK4, implicated in the pathogenesis of hypertension, is also linked to breast cancer.”

In 2002, a study of hypertension in mice revealed how a single nucleotide polymorphism (a change in one nucleotide in a DNA sequence) in the GRK4γ isoform increases GRK4 activity. This causes abnormal phosphorylation, altered D1R function, and subsequent changes in kidney sodium excretion. Three single nucleotide polymorphisms (SNPs) in the GRK4 gene, namely R65L, A142V, and A486V, have been identified, indicating GRK4 as a risk factor for hypertension.

Yue explores the role of GRK4 in breast cancer cell growth and proliferation. wonderisland/Shutterstock.com

GRK4 variants linked to increased breast cancer risk

In 2008, Matsubayashi and colleagues carried out a study to detect different GRK4 isoforms in disease and showed an increased expression of GRK4 in breast cancer compared to healthy breast tissue.

This study brought to light the involvement of GRK4 in breast cancer pathogenesis, highlighting the need for more research in this field. Further evidence came from experiments using differential allele-specific expression (DASE), a then-novel approach to identify genes associated with breast cancer risk. SNPs in GRK4, specifically R65L and A142V (the same identified as a risk for hypertension), were found to be associated with a higher risk of breast cancer, implicating GRK4 as a risk for both diseases. In addition, earlier studies demonstrated that overexpression of GRK4 leads to proliferation of breast cancer cells. The researchers also noted that the transcription factor, cMyc, regulates GRK4 expression in the kidney. cMyc is known to play an important role in cancer cell cellular processes.

G protein-coupled receptor kinase (GRK) regulates sodium excretion in the kidney. ibreakstock/Shutterstock.com

GRK4 promotes breast cancer cell proliferation

Yue and colleagues set out to better understand the role of GRK4 in breast cancer cell proliferation. Specifically, they explored the role of GRK4 in both breast cancer cells and samples from breast cancer patients. GRK4 was found in all seven breast cancer cell types but not in benign breast epithelial cells, consistent with previous findings. Of interest, in all except one of the breast cancer cell types, the GRK4 SNP A142V was identified, while three of the seven breast cancer cells carried the R65L SNP. Both SNPs are also associated with hypertension, suggesting an intrinsic link between GRK4, hypertension, and breast cancer. In addition, analysis of samples from breast cancer patients revealed that a SNP at R65L or A142V was three times more likely in breast cancer patients than in healthy individuals. Such SNPs are associated with increased GRK4 activity. This valuable data from breast cancer patients complements laboratory analyses of the seven breast cancer cell lines, strengthening the evidence linking GRK4, hypertension, and breast cancer risk.

Targeting GRK4 could halt breast cancer cell proliferation in diseased tissue, offering an effective treatment, particularly for breast cancer patients with hypertension. Gorodenkoff/Shutterstock.com

A focal point of the team’s study was to understand the role of GRK4 in breast cancer cell growth and proliferation. Through a series of experiments including an elegant study in cMyc knock-down breast cancer cells (where cMyc is not present), they demonstrated that increased GRK4 activity independently promotes growth of these cancer cells. This finding was confirmed in triple-negative breast cancer cells, where knock-down or reduction of GRK4 decreased cancer cell proliferation. Both sets of evidence confirm that GRK4 promotes cancer cell proliferation.

“Both sets of evidence confirm the cancer cell proliferation-promoting properties
of GRK4.”

The researchers were also able to distinguish differences in cell proliferation between the α and γ isoforms of GRK4 with the more abundant α isoform promoting cell proliferation more than the γ form. The γ isoform with three SNPs was as effective as the α isoform in stimulating cell proliferation, indicating that either high-level expression or SNPs could enhance the activity of GRK4.

Mechanistically, the study revealed that it is through promotion of cell proliferation and not alteration of apoptosis (programmed cell death) that GRK4 aids breast cancer growth. The findings of GRK4 over-expression in breast cancer cells and its independent promotion of breast cancer cell proliferation deepens our understanding of the pathological role of GRK4 and its mechanisms in breast cancer. This vital work unveils GRK4 as a potential target for breast cancer in addition to hypertension, and in doing so opens an avenue of therapeutics for further investigation.

Immunofluorescent staining of GRK4 (green) in T47D breast cancer cells.

GRK4: A therapeutic target

More studies are needed to determine the presence of GRK4 SNPs in breast cancer cells of patients, with and without hypertension, to further understand the associated risks. These study findings may have wider implications, and Yue and colleagues propose that GRK4 SNPs could play a role in other conditions, such as obesity. But what could this research mean for hypertensive and breast cancer patients? As GRK4 has limited expression in normal tissues, the researchers suggest that targeting GRK4 could halt breast cancer cell proliferation in diseased tissue, offering an effective treatment, particularly for breast cancer patients with hypertension.

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Aggressive triple-negative breast cancer (TNBC) has limited treatment options because of a lack of pathological proteins to target (no hormone receptors or HER2 proteins are implicated in this category of breast cancer). The team’s findings demonstrate a role for GRK4 in cancer cell proliferation in TNBC and suggest that targeting this molecule offers a potential therapy. Further research into the pathological mechanisms, as well as development and testing of potential GRK4 inhibitors, is now needed so that these findings may directly benefit patients in the future.

Are there plans to extend this research to explore GRK4 in other cancers besides breast cancer?
GRK4 is an ideal drug target because it is not ubiquitous in the human body and its increased expression and/or activity is associated with disease status. While we do find that GRK4 is up-regulated in colon cancer cells, our near-future plan is to find specific GRK4 inhibitors and explore their potential for the treatment of breast cancer and hypertension in the preclinical setting. We believe that a specific GRK4 inhibitor would provide a novel targeted therapy for breast cancer with relatively low side effects.

 

References

  • Yue, W, Gildea, JJ, Xu, P, Felder, RA, (2022) GRK4, A potential link between hypertension and breast cancer. Journal of Cell Science & Therapy, 13(2), 1000343. doi.org/10.35248/2157-7013-22.13.343
  • Yue, W, Tran, HT, Wang, J-P, et al, (2021) The hypertension related gene G protein-coupled receptor kinase 4 contributes to breast cancer proliferation. Breast Cancer: Basic and Clinical Research, 15, 1–8. doi.org/10.1177/11782234211015753
  • Gao, C, Devarajan, K, Zhou, Y, et al, (2012) Identifying breast cancer risk loci by global differential allele-specific expression (DASE) analysis in mammary epithelial transcriptome. BMC Genomics, 13, 570. doi.org/10.1186/1471-2164-13-570
  • Matsubayashi, J, Takanashi, M, Oikawa, K, et al, (2008) Expression of G protein-coupled receptor kinase 4 is associated with breast cancer tumorigenesis. Journal of Pathology, 216(3), 317–27. doi.org/10.1002/path.2414
  • Felder, RA, Sanada, H, Xu, J, et al, (2002) G protein-coupled receptor kinase 4 gene variants in human essential hypertension. Proc Natl Acad Sci USA, 99(6), 3872–7. doi.org/10.1002/path.2414
DOI
10.26904/RF-143-3039274260

Research Objectives

Wei Yue explores the relationship between hypertension, breast cancer, and the enzyme GRK4.

Funding

  • National Heart Lung and Blood Institute HL074940
  • National Institute of Diabetes and Digestive and Kidney Diseases DK039308

Collaborators

Robin A Felder, John J Gildea, Hanh T Tran, Peng Xu, Jiping Wang, and Katherine Schiermeyer

Bio

Wei Yue was awarded a doctoral degree in pharmacology from the University of Maryland School of Medicine. Her breast cancer research focuses on hormone-dependent breast cancer development, progression, treatment, and resistance to therapies. In recent years, she has expanded her studies to investigate the relationship between hypertension and breast cancer, with the aim of finding new targets to treat both diseases.

Wei Yue

Contact

E: wyue5mountain@yahoo.com
T: +1 434 227 /1247

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