Breast: Secretory Ductal Carcinoma

2004-08-01   Stevan Knezevich 

1.BC Cancer Research Centre (BCCRC), Vancouver, British Columbia, Canada

Summary

Atlas Image
Histology of index secretory breast carcinoma (SBC) case demonstrating well-differentiated but invasive glands containing eosinophilic secretions.

Classification

Note

Considered to be a subtype of infiltrating ductal carcinoma of the breast, but associated with a better prognosis.

Clinics and Pathology

Embryonic origin

Epithelial derived tumors, such as the breast carcinomas, arise from the Ectoderm.

Etiology

Our index case only demonstrated a t(12;15)(p13;q25) by cytogenetics, as seen in congenital fibrosarcoma (CFS) and the cellular variant of congenital mesoblastic nephroma (cCMN). Unlike CFS and cCMN, however, SBC did not show evidence of trisomy 11 which is found in virtually all cases of CFS and cCMN.

Epidemiology

Quite rare, with only a few reported cases.

Treatment

Simple mastectomy and axillary dissection.

Prognosis

The prognosis seems to correlate with age. The younger population has a 100% survival rate at 5-years, whereas the adult population with SBC has a much poorer prognosis on par with infiltrating ductal carcinoma.

Cytogenetics

Atlas Image
Partial karyogram demonstrating the t(12;15)(p13;q25) in secretory breast carcinoma occurring in a 6-year-old female. Arrowheads show breakpoints at derivative 12p13 and derivative 15q25.
Atlas Image
Dual color FISH using ETV6 exon 1-containing cosmid 179A6 (green) and ETV6 exon 8-containing cosmid 148B6. Arrows show separate signals indicating disruption of the ETV6 gene.

Genes Involved and Proteins

Gene name

ETV6 (ets variant 6)

Location

12p13.2

Dna rna description

9 exons; alternate splicing

Protein description

contains a Helix-Loop-Helix and ETS DNA binding domains; wide expression; nuclear localisation;. ETS-related transcription factor

Gene name

NTRK3 (neurotrophic tyrosine kinase, receptor, type 3)

Location

15q25.3

Dna rna description

20 exons, variant transcripts.

Protein description

extra-cellular ligand binding domain, a transmembrane domain, and an intracellular tyrosine kinase domain. Tyrosine kinase cell surface receptor.

Result of the chromosomal anomaly

Atlas Image
Schematic diagram showing the structure of the ETV6-NTRK3 chimeric cDNA in secretory breast carcinoma. Exons 1-5 of ETV6 (blue boxes) are fused in frame with exons 13-15 and 17-18 of NTRK3 (red boxes). The lighter shade of blue indicates the region encoding the ETV6 sterile-alpha-motif (SAM) domain, while the lighter shade of red indicates the region encoding the NTRK3 protein tyrosine kinase (PTK) domain. Numbers above the exons indicate the last nucleotide of each exon. The fusion point is between ETV6 nucleotide 1033 and NTRK3 nucleotide 1601 (indicated by the vertical arrow) which is identical to that observed in congenital fibrosarcoma. The positions of the TEL114 and TEL541 forward primers and the TRKC2 and TRK1 reverse primers used to characterize ETV6-NTRK3 fusion transcripts are shown under the exons (see text). An expanded view of the ETV6-NTRK3 breakpoint sequence in the index secretory breast carcinoma case is shown below the cDNA schematic. This was derived by sequencing of RT-PCR products using primers TEL-541 and TRKC2. Identical sequences were observed in multiple clones from three separate experiments. The vertical arrow shows the fusion point.
Atlas Image
The amino terminus is composed of the first 5 exons from ETV6, which carries the Helix-Loop-Helix Domain (HLH) responsible for dimerization. The remainder of the protein is composed of the Protein Tyrosine Kinase domain from NTRK3. The arrow represents the point at which the ETV6 contribution ends and the NTRK3 contribution begins.

Oncogenesis

Current speculation regarding the oncogenic mechanism of the fusion protein is related to its putative activation of the MAP Kinase pathway with resultant activation of various downstream proteins such as transcription factors. Native NTRK3 requires extracellular ligand binding of Neurotrophin 3 prior to its dimerization and autophosphorylation. ETV6-NTRK3, however, bypasses this requirement as it contains the HLH domain from ETV6 which allows the molecule to dimerize in the absence of Neurotrophin 3 and thus remain in a constitutively activated (phosphorylated) state. Once again, the presence of ETV6-NTRK3 seems to make these particular neoplasms behave more indolent than their aggressive Ductal Carcinoma counterparts, which do not harbor the ETV6-NTRK3 gene fusion.

Bibliography

Pubmed IDLast YearTitleAuthors
146919162003Secretory carcinoma of the breast: a distinct variant of invasive ductal carcinoma assessed by comparative genomic hybridization and immunohistochemistry.Diallo R et al
124507872002ETV6-NTRK3--Trk-ing the primary event in human secretory breast cancer.Euhus DM et al
151010492004A fluorescence in situ hybridization study of ETV6-NTRK3 fusion gene in secretory breast carcinoma.Makretsov N et al
145284412003Secretory carcinoma of the breast.Paeng MH et al
124507922002Expression of the ETV6-NTRK3 gene fusion as a primary event in human secretory breast carcinoma.Tognon C et al

External Links

Citation

Stevan Knezevich

Breast: Secretory Ductal Carcinoma

Atlas Genet Cytogenet Oncol Haematol. 2004-08-01

Online version: http://atlasgeneticsoncology.org/solid-tumor/5266/secretbreastcancid5266