PKCtheta promotes c-Rel-driven mammary tumorigenesis in mice and humans by repressing estrogen receptor alpha synthesis

Karine Belguise ¹, Gail E Sonenshein

⁰Department of Biochemistry and Women's Health Interdisciplinary Research Center, Boston University School of Medicine, Boston, Massachusetts 02118, USA.

The Journal of Clinical Investigation +

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November 27, 2007

View abstract on PubMed

Summary

Estrogen receptor alpha (ERalpha) normally suppresses c-Rel activity in breast cancer. A novel PKCtheta-Akt pathway downregulates ERalpha, releasing c-Rel to promote tumor growth and invasiveness.

Area Of Science

Molecular Biology
Cancer Research
Epigenetics

Background

Aberrant nuclear NF-kappaB c-Rel expression is common in human breast cancer.
While c-Rel plays a causal role in mammary tumorigenesis, its activation requires a secondary event due to long latency periods in mouse models.
Estrogen receptor alpha (ERalpha) signaling normally represses c-Rel activity in the mammary gland.

Purpose Of The Study

To elucidate the epigenetic mechanism by which c-Rel activity is derepressed in breast cancer.
To identify the pathway responsible for the downregulation of ERalpha synthesis.
To understand how this pathway contributes to breast cancer progression.

Main Methods

Analysis of ERalpha levels in c-Rel-induced mammary tumors versus normal mammary gland tissue.
Investigating the effect of PKCtheta on c-Rel activity and target gene expression in cell lines.
Correlating RNA expression levels of PKCtheta, c-Rel target genes, and ERalpha in human breast cancer specimens.
Examining the role of the PKCtheta-Akt pathway in regulating FOXO3a, ERalpha, and p27(Kip1) synthesis.

Main Results

ERalpha levels are significantly lower in c-Rel-induced mammary tumors.
PKCtheta activation enhances c-Rel activity, target gene expression, and proliferation in mammary tumor cell lines.
Expression of PKCtheta and c-Rel target genes is inversely correlated with ERalpha levels in human breast cancer.
The PKCtheta-Akt pathway inactivates FOXO3a, leading to decreased synthesis of ERalpha and p27(Kip1).

Conclusions

Activation of PKCtheta disrupts the FOXO3a/ERalpha/p27(Kip1) axis, which normally maintains an epithelial phenotype.
This disruption leads to the derepression of c-Rel and its target genes, promoting cancer cell proliferation, survival, and invasiveness.
The novel PKCtheta-Akt pathway represents a key epigenetic mechanism driving breast cancer progression.

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