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Differential expression of arrestins is a predictor of breast cancer progression and survival

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Abstract

Emerging evidence has implicated G protein-coupled receptors, such as CXCR4 and PAR2, in breast cancer progression and the development of metastatic breast cancer. However, the role of proteins that regulate the function of these receptors, such as arrestins, in breast cancer has yet to be determined. Examination of the expression of the two nonvisual arrestins, arrestin2 and 3, in various breast cancer cell lines revealed comparable expression of arrestin3 in basal and luminal lines while arrestin2 expression was much higher in the luminal lines compared to the more aggressive basal lines. Analysis of normal human breast tissue revealed that arrestin2 and 3 were expressed in both luminal and myoepithelial cells of mammary epithelia with arrestin2 highest in myoepithelial cells and arrestin3 comparable in both cell types. Quantitative immunofluorescence-based examination of primary breast tumors revealed that arrestin2 expression significantly decreased with cancer progression from ductal carcinoma in situ to invasive carcinoma and further to lymph node metastasis (P < 0.001). Moreover, decreased arrestin2 expression was associated with decreased survival (P = 0.0007) as well as positive lymph node status and increased tumor size and nuclear grade. In contrast, arrestin3 expression significantly increased during breast cancer progression (P < 0.001) and increased expression was associated with decreased survival (P = 0.014). Arrestin3 was also an independent prognostic marker of breast cancer with a hazard ratio of 1.65. Overall, these studies demonstrate that arrestin2 levels decrease while arrestin3 levels increase during breast cancer progression and these changes correlate with a poor clinical outcome.

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Abbreviations

AQUA:

Automated quantitative analysis

BP:

Blocking peptide

CEMA:

Cutting edge matrix assembly

DAB:

3,3′-Diaminobenzidine

DAPI:

4′,6-Diamidino-2-phenylindole

DCIS:

Ductal carcinoma in situ

ER:

Estrogen receptor

ERK2:

Extracellular signal-regulated kinase 2

FBS:

Fetal bovine serum

GPCR:

G protein-coupled receptor

GST:

Glutathione S-Transferase

HER2+:

Human epidermal growth factor receptor 2

HR:

Hazard ratio

HRP:

Horseradish peroxidase

IDC:

Invasive ductal carcinoma

IGF-1R:

Insulin-like growth factor 1 receptor

IHC:

Immunohistochemistry

PR:

Progesterone receptor

TBS:

Tris buffered saline

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Aknowledgements

We would like to thank Dr. Catherine Moore for helping to initiate some of the studies in the breast cancer cell lines and Shashi Rattan for excellent technical assistance. This work was partially supported by National Institutes of Health grants R01 CA129626 and R01 GM047417. The authors declare that there are no conflicts-of-interest.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Thomas Jefferson University, 233 South 10th Street, Philadelphia, PA, 19107, USA

    Allison M. Michal & Jeffrey L. Benovic

  2. Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, 19107, USA

    Amy R. Peck, Thai H. Tran, Chengbao Liu & Hallgeir Rui

  3. Department of Pathology, Yale University School of Medicine, New Haven, CT, 06520, USA

    David L. Rimm

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  1. Allison M. Michal
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  2. Amy R. Peck
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Correspondence to Jeffrey L. Benovic.

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Michal, A.M., Peck, A.R., Tran, T.H. et al. Differential expression of arrestins is a predictor of breast cancer progression and survival. Breast Cancer Res Treat 130, 791–807 (2011). https://doi.org/10.1007/s10549-011-1374-9

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  • DOI: https://doi.org/10.1007/s10549-011-1374-9

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