Metaplastic breast carcinomas are basal-like breast cancers: a genomic profiling analysis.
BACKGROUND
Metaplastic breast carcinomas (MBCs) comprise a group of aggressive and chemotherapy resistant cancers characterised by neoplastic cells displaying differentiation towards squamous epithelium or mesenchymal elements. Previous histopathological and immunohistochemical analysis of MBCs suggested that these cancers would have a basal-like profile.


METHODS
We investigated the molecular subtype of 20 MBCs using microarray-based expression profiling data. These data were compared with those of 79 invasive ductal carcinomas (IDCs) of basal-like phenotype by unsupervised hierarchical clustering, supervised analysis and pathway analysis.


RESULTS
We demonstrate that 95% of all MBCs are of basal-like molecular subtype. Furthermore, unsupervised hierarchical clustering analysis and pathway analysis of the profiles of MBCs revealed that MBCs are part of the spectrum of basal-like breast cancers. Significance analysis of microarrays (SAM) identified 1,385 transcripts differentially expressed between MBCs and IDCs of basal-like phenotype. Pathway analysis using these genes revealed that DNA repair pathways, including BRCA1 pathway, PTEN, a gene whose loss of function is associated with resistance to chemotherapy, and TOP2A, the molecular target of anthracyclines, are significantly downregulated in MBCs compared to basal-like IDCs. These findings may at least in part explain the reported poor responses to chemotherapy of MBCs. Furthermore, MBCs showed significantly higher expression of genes related to myoepithelial differentiation and epithelial to mesenchymal transition (EMT).


CONCLUSIONS
Our results demonstrate that MBCs are part of the spectrum of basal-like breast carcinomas and display a myoepithelial and EMT-like molecular make-up. The reported poorer response to chemotherapeutic agents in patients with MBCs may stem from downregulated DNA damage response pathways, PTEN and TOP2A.
Weigelt
Britta
B
Life Sciences Division, Ernest Orlando Lawrence Berkeley National Laboratory, 1 Cyclotron Road, MS-977-225A, Berkeley, CA 94720, USA. bweigelt@lbl.gov
Kreike
Bas
B
Reis-Filho
Jorge S
JS
D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D018270:Carcinoma, Ductal, Breast / Q000235:genetics* / Q000473:pathology*; D004250:DNA Topoisomerases, Type II / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D008679:Metaplasia; D020411:Oligonucleotide Array Sequence Analysis; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D000075223:Poly-ADP-Ribose Binding Proteins
D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D051059:PTEN Phosphohydrolase; D004250:DNA Topoisomerases, Type II; C000618811:TOP2A protein, human