Abstract
Triple-negative breast cancer (TNBC) patients with upregulated Wnt/β-catenin signaling often have poor clinical prognoses. During pathological examinations of breast cancer sections stained for β-catenin, we made the serendipitous observation that relative to non-TNBC, specimens from TNBC patients have a greater abundance of nucleoli. There was a remarkable direct relationship between nuclear β-catenin and greater numbers of nucleoli in TNBC tissues. These surprising observations spurred our investigations to decipher the differential functional relevance of the nucleolus in TNBC versus non-TNBC cells. Comparative nucleolar proteomics revealed that the majority of the nucleolar proteins in TNBC cells were potential targets of β-catenin signaling. Next, we undertook an analysis of the nucleolar proteome in TNBC cells in response to β-catenin inhibition. This effort revealed that a vital component of pre-rRNA processing, LAS1 like ribosome biogenesis factor (LAS1L) was significantly decreased in the nucleoli of β-catenin inhibited TNBC cells. Here we demonstrate that LAS1L protein expression is significantly elevated in TNBC patients, and it functionally is important for mammary tumor growth in xenograft models and enables invasive attributes. Our observations highlight a novel function for β-catenin in orchestrating nucleolar activity in TNBCs.
Highlights
The nucleolus is a non-membrane-bound, subnuclear body that is known primarily for its role in ribosome biogenesis
In order to examine if this characteristic increase in nucleolar number is reflected in human breast cancer cell lines, we analyzed the nucleolar numbers from six Triple-negative breast cancer (TNBC) and six non-TNBC cell lines using NucleolarID stain (Fig. 1D)
We found that TNBC cell lines had significantly (p < 0.001) more nucleoli per nucleus than nonTNBC cell lines (Fig. 1E)
Summary
The nucleolus is a non-membrane-bound, subnuclear body that is known primarily for its role in ribosome biogenesis. The nucleolus forms around nucleolar organizer regions (NORs). It is composed of three distinct sub-compartments, the fibrillar center, the dense fibrillar component, and the granular component, each of which is responsible for different aspects of ribosome biogenesis. Ribosomes are the macromolecular ensembles of ribosomal RNA (rRNA) and ribosomal proteins. Ribosomal DNA (rDNA) codes for rRNA and is located as tandemrepeats on five acrocentric chromosomes (chromosomes #13,14,15, 21, and 22). The transcription of rDNA is Official journal of the Cell Death Differentiation Association
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