Ectopic runx2 expression in mammary epithelial cells disrupts formation of normal acini structure: implications for breast cancer progression.
The transcription factor Runx2 is highly expressed in breast cancer cells compared with mammary epithelial cells and contributes to metastasis. Here we directly show that Runx2 expression promotes a tumor cell phenotype of mammary acini in three-dimensional culture. Human mammary epithelial cells (MCF-10A) form polarized, growth-arrested, acini-like structures with glandular architecture. The ectopic expression of Runx2 disrupts acini formation, and electron microscopic ultrastructural analysis revealed the absence of lumens. Characterization of the disrupted acini structures showed increased cell proliferation (Ki-67 positive cells), decreased apoptosis (Bcl-2 induction), and loss of basement membrane formation (absence of beta(4) integrin expression). In complementary experiments, inhibition of Runx2 function in metastatic MDA-MB-231 breast cancer cells by stable expression of either short hairpin RNA-Runx2 or a mutant Runx2 deficient in subnuclear targeting resulted in reversion of acini to more normal structures and reduced tumor growth in vivo. These novel findings provide direct mechanistic evidence for the biological activity of Runx2, dependent on its subnuclear localization, in promoting early events of breast cancer progression and suggest a molecular therapeutic target.
Pratap
Jitesh
J
Department of Cell Biology and Cancer Center, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.
Imbalzano
Karen M
KM
Underwood
Jean M
JM
Cohet
Nathalie
N
Gokul
Karthiga
K
Akech
Jacqueline
J
van Wijnen
Andre J
AJ
Stein
Janet L
JL
Imbalzano
Anthony N
AN
Nickerson
Jeffrey A
JA
Lian
Jane B
JB
Stein
Gary S
GS
D001943:Breast Neoplasms / Q000235:genetics; D018929:Cell Culture Techniques; D002465:Cell Movement; D016764:Cell Polarity; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D050659:Core Binding Factor Alpha 1 Subunit / Q000096:biosynthesis* / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D021621:Imaging, Three-Dimensional; D042361:Mammary Glands, Human / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D009362:Neoplasm Metastasis
D050659:Core Binding Factor Alpha 1 Subunit; C493709:RUNX2 protein, human
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