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The docking protein Gab2 is overexpressed and estrogen regulated in human breast cancer
Roger J Daly1, Haihua Gu, Jayamala Parmar
1Cancer Research Program, Garvan Institute of Medical Research, St Vincent's Hospital, Sydney, NSW 2010, Australia. r.daly@garvan.org.edu
Abstract:
Grb2-associated binder 2 (Gab2) is a recently identified member of the Gab/Daughter of sevenless family of docking proteins, which localize, amplify and integrate signaling pathways activated by various receptors including receptor tyrosine kinases (RTKs). To date, Gab2 signaling has been primarily investigated in hematopoietic cells. Here we report marked overexpression of Gab2 in a subset of breast cancer cell lines relative to normal breast epithelial strains and a trend for increased Gab2 expression in estrogen receptor (ER)-positive lines. Overexpression relative to normal ductal epithelium was also observed in some primary breast cancers. In MCF-7 breast cancer cells Gab2 was markedly tyrosine phosphorylated in response to heregulin and also following EGF, insulin or bFGF administration, indicating that a variety of RTKs implicated in breast cancer development or progression couple to this docking protein. In hormone-responsive breast cancer cells, GAB2 mRNA and protein expression were induced by estradiol in a manner sensitive to the pure anti-estrogen ICI 182780, indicating that this regulation is mediated via the ER. Gab2 therefore represents a novel link between steroid and growth factor signaling in breast cancer, and when overexpressed, may modulate the sensitivity of breast cancer cells to these important growth regulators.
Insights
Grb2-associated binder 2 (Gab2) is overexpressed in some breast cancers, linking steroid and growth factor signaling. This docking protein may influence breast cancer cell sensitivity to growth regulators.
Area of Science:
- Oncology
- Molecular Biology
- Cell Signaling
Background:
- Gab2 is a docking protein that integrates signaling pathways activated by receptor tyrosine kinases (RTKs).
- Gab2 signaling has been mainly studied in hematopoietic cells.
- Overexpression of Gab2 is observed in a subset of breast cancer cell lines and primary tumors.
Purpose of the Study:
- To investigate the role and regulation of Gab2 in breast cancer.
- To determine if Gab2 links steroid and growth factor signaling pathways in breast cancer.
Main Methods:
- Quantitative analysis of Gab2 expression in breast cancer cell lines and primary tumors.
- Assessment of Gab2 tyrosine phosphorylation in response to various growth factors (heregulin, EGF, insulin, bFGF).
- Analysis of GAB2 mRNA and protein expression regulation by estradiol and anti-estrogen (ICI 182780) in hormone-responsive breast cancer cells.
Main Results:
- Gab2 is markedly overexpressed in a subset of breast cancer cell lines compared to normal breast epithelial cells.
- A trend for increased Gab2 expression was observed in estrogen receptor (ER)-positive breast cancer lines.
- Gab2 is tyrosine phosphorylated in response to multiple RTKs implicated in breast cancer.
- Estradiol induces GAB2 mRNA and protein expression via the ER in hormone-responsive breast cancer cells.
Conclusions:
- Gab2 is a novel link between steroid and growth factor signaling in breast cancer.
- Overexpressed Gab2 may modulate breast cancer cell sensitivity to growth regulators.
- Gab2 represents a potential therapeutic target in specific breast cancer subtypes.