GATA3 targets semaphorin 3B in mammary epithelial cells to suppress breast cancer progression and metastasis

• Published in: Oncogene Vol. 36; no. 40; pp. 5567 - 5575
• Main Authors: Shahi, P, Wang, C-Y, Chou, J, Hagerling, C, Gonzalez Velozo, H, Ruderisch, A, Yu, Y, Lai, M-D, Werb, Z
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05-10-2017; Nature Publishing Group
• Subjects: 13/1; 13/106; 13/21; 13/31; 13/51; 14/63; 64/60; 692/53/2422; 692/53/2423; 82; Animals; Apoptosis; Axon guidance; Breast - metabolism; Breast - pathology; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Care and treatment; Cell Biology; Cell differentiation; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cellular biology; Diagnosis; Disease Progression; Epithelial cells; Epithelial Cells - metabolism; Female; GATA-3 protein; GATA3 Transcription Factor - metabolism; Gene expression; Gene Expression Regulation, Neoplastic; Homeostasis; Human Genetics; Internal Medicine; LIM kinase; Lim Kinases - metabolism; Mammary gland; Medicine; Medicine & Public Health; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Metastases; Metastasis; Mice, Nude; Neoplasm Metastasis; Oncology; original-article; Phenotypes; Prognosis; Semaphorins - genetics; Semaphorins - metabolism; Signal Transduction; Tumor suppressor genes; Tumor Suppressor Proteins - metabolism
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2017.165

Semaphorin 3B (SEMA3B) is a secreted axonal guidance molecule that is expressed during development and throughout adulthood. Recently,
SEMA3B
has emerged as a tumor suppressor in non-neuronal cells. Here, we show that
SEMA3B
is a direct target of GATA3 transcriptional activity. GATA3 is a key transcription factor that regulates genes involved in mammary luminal cell differentiation and tumor suppression. We show that GATA3 relies on
SEMA3B
for suppression of tumor growth. Loss of
SEMA3B
renders GATA3 inactive and promotes aggressive breast cancer development. Overexpression of
SEMA3B
in cells lacking GATA3 induces a GATA3-like phenotype and higher levels of
SEMA3B
are associated with better cancer patient prognosis. Moreover,
SEMA3B
interferes with activation of LIM kinases (LIMK1 and LIMK2) to abrogate breast cancer progression. Our data provide new insights into the role of
SEMA3B
in mammary gland and provides a new branch of GATA3 signaling that is pivotal for inhibition of breast cancer progression and metastasis.