GATA3 inhibits breast cancer growth and pulmonary breast cancer metastasis.
The loss of expression of the transcription factor GATA3 in breast tumors has been linked to aggressive tumor development and poor patient survival. In the present work, we address potential roles for GATA3 in breast tumor lung metastasis and progression. Using an aggressive breast cancer cell line, which metastasizes specifically to the lung, we show that GATA3 expression results in reduced tumor outgrowth in the mammary fat pad and lower lung metastatic burden in nude mice. Specifically, GATA3 expression inhibits breast cancer cell expansion inside the lung parenchyma. This phenotype correlates with the ability of GATA3 to negatively regulate the expression of several genes that promote breast cancer lung metastasis (ID1/-3, KRTHB1, LY6E and RARRES3). Conversely, the expression of genes encoding known inhibitors of lung metastasis (DLC1 (deleted in liver cancer 1) and PAEP (progestagen-associated endometrial protein)) is upregulated by GATA3. These data correlate with microarray data from human breast cancer patients, showing a strong correlation between high GATA3 expression and absence of metastases specifically to the lungs. We conclude that GATA3 inhibits primary breast tumor outgrowth and reduces lung metastatic burden by regulating key genes involved in metastatic breast tumor progression.
Dydensborg
A B
AB
Biochemistry Department, Goodman Cancer Centre, McGill University, Quebec, Canada.
Rose
A A N
AA
Wilson
B J
BJ
Grote
D
D
Paquet
M
M
Giguère
V
V
Siegel
P M
PM
Bouchard
M
M
D000818:Animals; D000954:Antigens, Surface / Q000235:genetics; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D005260:Female; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D058851:GPI-Linked Proteins; D020690:GTPase-Activating Proteins; D015972:Gene Expression Regulation, Neoplastic; D000071816:Glycodelin; D006023:Glycoproteins / Q000235:genetics; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000235:genetics; D053564:Keratins, Hair-Specific / Q000235:genetics; D053531:Keratins, Type II / Q000235:genetics; D008175:Lung Neoplasms / Q000235:genetics* / Q000556:secondary*; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D011257:Pregnancy Proteins / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics; D015854:Up-Regulation
D000954:Antigens, Surface; C112352:DLC1 protein, human; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; D058851:GPI-Linked Proteins; D020690:GTPase-Activating Proteins; D000071816:Glycodelin; D006023:Glycoproteins; C497453:ID1 protein, human; D051798:Inhibitor of Differentiation Protein 1; C507600:KRT81 protein, human; D053564:Keratins, Hair-Specific; D053531:Keratins, Type II; C439870:LY6E protein, human; D008565:Membrane Proteins; C045246:PAEP protein, human; C437968:PLAAT4 protein, human; D011257:Pregnancy Proteins; D018168:Receptors, Retinoic Acid; D025521:Tumor Suppressor Proteins