GATA3 inhibits breast cancer growth and pulmonary breast cancer metastasis

• Published in: Oncogene Vol. 28; no. 29; pp. 2634 - 2642
• Main Authors: Dydensborg, A B, Rose, A A N, Wilson, B J, Grote, D, Paquet, M, Giguère, V, Siegel, P M, Bouchard, M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23.07.2009; Nature Publishing Group
• Subjects: Animals; Antigens, Surface - genetics; Apoptosis; Biological and medical sciences; Breast cancer; Breast Neoplasms - pathology; Cell Biology; Cell Line, Tumor; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cellular biology; DNA binding proteins; DNA microarrays; Endometrium; Female; Fundamental and applied biological sciences. Psychology; GATA-3 protein; GATA3 Transcription Factor - genetics; GATA3 Transcription Factor - metabolism; Gene expression; Gene Expression Regulation, Neoplastic; Genetic aspects; Genetics; Glycodelin; Glycoproteins - genetics; GPI-Linked Proteins; GTPase-Activating Proteins; Gynecology. Andrology. Obstetrics; Human Genetics; Humans; Id1 protein; Inhibitor of Differentiation Protein 1 - genetics; Internal Medicine; Keratins, Hair-Specific - genetics; Keratins, Type II - genetics; Liver cancer; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - secondary; Mammary gland diseases; Medical sciences; Medicine; Medicine & Public Health; Membrane Proteins - genetics; Metastases; Metastasis; Mice; Mice, Nude; Molecular and cellular biology; Oncology; original-article; Parenchyma; Phenotypes; Physiological aspects; Pregnancy Proteins - genetics; Receptors, Retinoic Acid - genetics; Risk factors; Tumor Suppressor Proteins - genetics; Tumors; Up-Regulation; Canada; breast cancer; lung metastasis; GATA3; Mammary gland diseases; Lung disease; Breast disease; Lung metastasis; Respiratory disease; Growth; Breast cancer; Malignant tumor; Inhibition; Carcinogenesis; Cancer
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2009.126

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.