Heregulin Induces Phosphorylation of BRCA1 through Phosphatidylinositol 3-Kinase/AKT in Breast Cancer Cells

Soner Altiok,David Batt,Nedret Altiok,Anna Papautsky,Julian Downward,Thomas M Roberts,Hava Avraham

doi:10.1074/jbc.274.45.32274

Abstract

The breast cancer susceptibility gene BRCA1 encodes a nuclear phosphoprotein that acts as a tumor suppressor. Phosphorylation of BRCA1 has been implicated in altering its function, however, the pathway(s) that leads to the phosphorylation of BRCA1 has not been described. Here, a signaling pathway by which heregulin induces cell cycle-independent phosphorylation of BRCA1 was delineated. We showed that heregulin stimulation induced the phosphorylation of BRCA1 and concomitant activation of the serine/threonine kinase AKT in T47D human breast cancer cells. Heregulin-induced phosphorylation of BRCA1 was abrogated by phosphatidylinositol 3-kinase (PI3K) inhibitors and by a dominant-negative AKT. In the absence of heregulin, the ectopic expression of the constitutively active p110 subunit of PI3K was sufficient to induce BRCA1 phosphorylation. Furthermore, the purified glutathione S-transferase/AKT kinase phosphorylated BRCA1 in vitro. We have also shown that the phosphorylation of BRCA1 by AKT occurs on the residue Thr-509, which is located in the nuclear localization signal. These results reveal a novel signaling pathway that links extracellular signals to the phosphorylation of BRCA1 in breast cancer cells.

Highlights

Heregulins (NDF/neuregulin) are a group of growth factors that regulate growth, differentiation, and survival of various breast cancer cell lines [1]
Treatment of T47D Cells by Heregulin Leads to Phosphorylation of BRCA1—Heregulin overexpression has been shown to induce aggressive tumor growth in breast cancer cells by activating the ErbB-2, ErbB-3, and ErbB-4 receptor signaling cascades (20 –22)
To investigate whether the tumor suppressor protein BRCA1 is a downstream target of the ErbB signaling pathway in breast cancer cells, BRCA1 immunoprecipitates were prepared from whole cell lysates of serum-starved T47D cells untreated or treated with heregulin for different time periods

Summary

Introduction

Heregulins (NDF/neuregulin) are a group of growth factors that regulate growth, differentiation, and survival of various breast cancer cell lines [1]. A signaling pathway by which heregulin induces cell cycle-independent phosphorylation of BRCA1 was delineated. We showed that heregulin stimulation induced the phosphorylation of BRCA1 and concomitant activation of the serine/threonine kinase AKT in T47D human breast cancer cells.

Results

Conclusion