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Loss of the retinoblastoma tumor suppressor is a common event in Basal-like and Luminal B breast carcinomas

ABSTRACT: Breast cancers can be classified using whole genome expression into distinct subtypes that show differences in patient prognosis. One of these groups, the basal-like carcinomas, are poorly differentiated, highly metastatic, and genomically unstable. These tumors also contain specific genetic alterations with one example being frequent p53 mutations. The loss of the tumor suppressor gene encoded by the retinoblastoma (RB1) locus is a well-characterized occurrence in many tumor types, however, its role in breast cancer is less clear with many reports demonstrating a Loss of Heterozygosity (LOH) that does not correlate with loss of RB1 protein expression. Here we report that LOH of the RB1 locus was observed at a high frequency in basal-like and luminal B tumors. These tumors also concurrently have low expression of RB1 mRNA as assessed by DNA microarray. As in previous reports, we also did not see a significant correlation between RB1 LOH and protein expression as measured by immunohistochemistry (IHC). p16INK4a, however, was highly expressed both by microarray and IHC, in basal-like tumors only presumably due to a previously reported feedback loop caused by RB1 loss. These results suggest that the functional loss of RB1 is a common event in the progression of basal-like and luminal B breast tumors, which may play a key role in dictating therapeutic responses Keywords: reference x sample

ORGANISM(S): Homo sapiens

PROVIDER: GSE10884 | GEO | 2008/09/18

SECONDARY ACCESSION(S): PRJNA107279

REPOSITORIES: GEO

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Project description:Breast cancer is a heterogeneous disease comprised of at least five major subtypes. Luminal subtype tumors confer a more favourable patient prognosis, which is in part, attributed to the Estrogen Receptor-alpha (ER) positivity and anti-hormone responsiveness of these tumors. Expression of the forkhead box transcription factor, FOXA1, also correlates with the luminal subtype and patient survival, but is present in a subset of ER-negative tumors. Similarly, FOXA1 is consistently expressed in luminal breast cancer cell lines even in the absence of ER. In contrast, basal breast cancer cell lines do not express FOXA1, and loss of FOXA1 in luminal cells increases migration and invasion, characteristics of the basal subtype. To delineate an ER-independent role for FOXA1 in maintaining the luminal phenotype, and hence a more favourable prognosis, we performed cDNA microarray analyses on luminal FOXA1-positive, ER-positive (MCF7, T47D) and FOXA1-positive, ER-negative (MDA-MB-453, SKBR3) cell lines in the presence or absence of transient FOXA1 silencing. This resulted in three FOXA1 transcriptomes: (1) a luminal-signature (consistent across cell lines), (2) an ER-positive signature (restricted to MCF7 and T47D) and (3) an ER-negative signature (restricted to MDA-MB-453 and SKBR3). Use of Gene Set Enrichment Analyses (GSEA) as a phenotyping tool revealed that FOXA1 silencing resulted in a transcriptome shift from luminal to basal gene expression signatures. FOXA1 binds to both luminal and basal genes within luminal breast cancer cells, suggesting that it not only transactivates luminal genes, but also represses basal-associated genes. From these results we conclude that FOXA1 controls plasticity between basal and luminal cells, playing a dominant role in repressing the basal phenotype, and thus tumor aggressiveness, in luminal breast cancer cells. Although it has been proposed that FOXA1-targeting agents may be useful for treating luminal tumors, these data suggest that this approach may promote transitions toward a more aggressive cancer. FOXA1 siRNA treated breast cell lines compared directly to nonspecific siRNA treated cell lines using Agilent 4X44 microarrays.

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Loss of the retinoblastoma tumor suppressor is a common event in Basal-like and Luminal B breast carcinomas

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