The docking protein Gab2 is overexpressed and estrogen regulated in human breast cancer.
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.
Daly
Roger J
RJ
Cancer Research Program, Garvan Institute of Medical Research, St Vincent's Hospital, Sydney, NSW 2010, Australia. r.daly@garvan.org.edu
Gu
Haihua
H
Parmar
Jayamala
J
Malaney
Suzann
S
Lyons
Ruth J
RJ
Kairouz
Rania
R
Head
Darren R
DR
Henshall
Susan M
SM
Neel
Benjamin G
BG
Sutherland
Robert L
RL
D048868:Adaptor Proteins, Signal Transducing; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D004958:Estradiol / Q000378:metabolism / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D013997:Time Factors; D014407:Tumor Cells, Cultured
D048868:Adaptor Proteins, Signal Transducing; C490895:GAB2 protein, human; D010750:Phosphoproteins; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D004958:Estradiol