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Mutant GATA3 Actively Promotes the Growth of Normal and Malignant Mammary Cells.

ABSTRACT: GATA3, a transcription factor expressed in luminal breast epithelial cells, is required for mammary gland development. Heterozygous GATA3 mutations occur in up to 15% of estrogen receptor (ER)-positive breast tumors and have been proposed to be null alleles resulting in haploinsufficiency; however, the mutation spectrum of GATA3 in breast cancer is in sharp contrast to that found in HDR syndrome, a true GATA3 haploinsufficiency disease.Transgenic mice, 3D cultures and xenografts were used to examine the effect of mutant GATA3 expression on mammary cell proliferation.Mutant GATA3 accelerated tumor growth of ZR751 cell xenografts and promoted precocious lobuloalveolar development in transgenic mouse mammary glands.GATA3 mutations, recently observed in breast cancer, encode active transcription factors, which elicit proliferative phenotypes in normal mammary epithelium and promote the growth of ER-positive breast cancer cell lines.

SUBMITTER: Emmanuel N

PROVIDER: S-EPMC6092927 | biostudies-other | 2018 Aug

REPOSITORIES: biostudies-other

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Mutant GATA3 Actively Promotes the Growth of Normal and Malignant Mammary Cells.

Emmanuel Natasha N Lofgren Kristopher A KA Peterson Esther A EA Meier David R DR Jung Eric H EH Kenny Paraic A PA

Anticancer research 20180801 8

<h4>Background/aim</h4>GATA3, a transcription factor expressed in luminal breast epithelial cells, is required for mammary gland development. Heterozygous GATA3 mutations occur in up to 15% of estrogen receptor (ER)-positive breast tumors and have been proposed to be null alleles resulting in haploinsufficiency; however, the mutation spectrum of GATA3 in breast cancer is in sharp contrast to that found in HDR syndrome, a true GATA3 haploinsufficiency disease.<h4>Materials and methods</h4>Transge ...[more]

PMID: 30061207

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Project description:MicroRNAs (miRNAs) in body fluids are candidate diagnostics for a variety of conditions and diseases, including breast cancer. One premise for using extracellular miRNAs to diagnose disease is the notion that the abundance of the miRNAs in body fluids reflects their abundance in the abnormal cells causing the disease. As a result, the search for such diagnostics in body fluids has focused on miRNAs that are abundant in the cells of origin. Here we report that released miRNAs do not necessarily reflect the abundance of miRNA in the cell of origin. We find that release of miRNAs from cells into blood, milk and ductal fluids is selective and that the selection of released miRNAs may correlate with malignancy. In particular, the bulk of miR-451 and miR-1246 produced by malignant mammary epithelial cells was released, but the majority of these miRNAs produced by non-malignant mammary epithelial cells was retained. Our findings suggest the existence of a cellular selection mechanism for miRNA release and indicate that the extracellular and cellular miRNA profiles differ. This selective release of miRNAs is an important consideration for the identification of circulating miRNAs as biomarkers of disease. miRNA microarrays were screened by LC Sciences. One microgram of MCF7 cellular RNA preparation was labeled with Cy3, and one microgram of the extracellular RNA samples was labeled with Cy5. In brief, the RNA was labeled with Cy5 or Cy3 and hybridized to LCSciences standard arrays for mature miRNA of all species available in the Sanger miRBase database (Release 12.0). The data were analyzed including background subtraction, using a LOWESS (locally weighted regression) method on the background-subtracted data. Only transcripts with a signal intensity higher than 3X (background SD) and spot CV<0.5. CV was calculated by (SD)/(signal intensity), and in which repeating probes on the array produced signals from at least 50% of the repeating probes are above detection level.

Dataset Information

Mutant GATA3 Actively Promotes the Growth of Normal and Malignant Mammary Cells.

Publications

Mutant GATA3 Actively Promotes the Growth of Normal and Malignant Mammary Cells.

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