Prolactin and heregulin override DNA damage-induced growth arrest and promote phosphatidylinositol-3 kinase-dependent proliferation in breast cancer cells.

Abstract

Heregulin (HRG), a ligand of ErbB receptor tyrosine kinases, is a potent mitogenic factor for breast cancer cells. Prolactin (PRL) has also been reported to regulate proliferation in breast cancer cells through its receptor, a member of the type I cytokine receptor family. Cytokine receptors are potent mitogens in hematopoietic cells, where they also override DNA damage-induced growth arrest checkpoints through activation of a phosphatidylinositol-3 kinase (PI3K) signaling pathway. In this study, we assessed the effect of gamma-irradiation on the mitogenic activity of HRG and PRL in breast cancer cells. HRG and PRL enhanced the proliferation of non-irradiated breast cancer cell lines in association with their ability to activate PI3K signaling pathways. Both growth factors also overrode irradiation-induced growth arrest in T47D cells, which resulted in decreased viability after irradiation. An inhibitor of PI3K, LY294002, abrogated growth factor-induced proliferation and the activity of cell cycle-dependent kinases in non-irradiated and irradiated cells. Thus, growth factors acting through distinct receptor families share a similar PI3K-dependent ability to promote proliferation and override DNA damage-induced growth arrest in breast cancer cells. These observations also suggest that selective activation of PI3K-dependent signaling can enhance radiosensitivity in breast cancer cells.

• Authors: Paula Chakravarti, Matthew K Henry, Frederick W Quelle
• Journal: International journal of oncology (Int J Oncol) Vol. 26 Issue 2 Pg. 509-14 (Feb 2005) ISSN: 1019-6439 [Print] Greece
• PMID: 15645137 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Chromones
• Growth Substances
• Morpholines
• Neuregulin-1
• 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
• Prolactin
• DNA
• Phosphatidylinositol 3-Kinases

Topics

• Blotting, Western
• Breast Neoplasms (metabolism)
• Cell Cycle
• Cell Line, Tumor
• Cell Proliferation
• Cell Survival
• Chromones (pharmacology)
• DNA (metabolism)
• DNA Damage
• Gene Expression Regulation, Neoplastic
• Growth Substances
• Humans
• Morpholines (pharmacology)
• Neuregulin-1 (physiology)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphorylation
• Prolactin (physiology)
• Signal Transduction