Genomic alterations associated with early stages of breast tumor metastasis.
BACKGROUND
Molecular studies suggest that acquisition of metastatic potential occurs early in the development of breast cancer; mechanisms by which cells disseminate from the primary carcinomas and successfully colonize foreign tissues are, however, largely unknown. Thus, we examined levels and patterns of chromosomal alterations in primary breast tumors from node-negative (n = 114) and node-positive (n = 115) patients to determine whether specific genomic changes are associated with tumor metastasis.


METHODS
Fifty-two genetic markers representing 26 chromosomal regions commonly altered in breast cancer were examined in laser microdissected tumor samples to assess levels and patterns of allelic imbalance (AI). Real time-PCR (RT-PCR) was performed to determine expression levels of candidate genes. Data was analyzed using exact unconditional and Student's t-tests with significance values of P < 0.05 and P < 0.002 used for the clinicopathological and genomic analyses, respectively.


RESULTS
Overall levels of AI in primary breast tumors from node-negative (20.8%) and node-positive (21.9%) patients did not differ significantly (P = 0.291). When data were examined by chromosomal region, only chromosome 8q24 showed significantly higher levels (P < 0.0005) of AI in node-positive primary tumors (23%) versus node-negative samples (6%). c-MYC showed significantly higher levels of gene expression in primary breast tumors from patients with lymph node metastasis.


CONCLUSIONS
Higher frequencies of AI at chromosome 8q24 in patients with positive lymph nodes suggest that genetic changes in this region are important to the process of metastasis. Because overexpression of c-MYC has been associated with cellular dissemination as well as development of the premetastatic niche, alterations of the 8q24 region, including c-MYC, may be key determinants in the development of lymph node metastasis.
Ellsworth
Rachel E
RE
Clinical Breast Care Project, Henry M. Jackson Foundation for the Advancement of Military Medicine, 620 Seventh Street, Windber, PA 15963, USA. r.ellsworth@wriwindber.org
Ellsworth
Darrell L
DL
Patney
Heather L
HL
Deyarmin
Brenda
B
Hooke
Jeffrey A
JA
Love
Brad
B
Shriver
Craig D
CD
D022981:Allelic Imbalance / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology / Q000556:secondary; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005819:Genetic Markers; D016678:Genome; D006801:Humans; D008207:Lymphatic Metastasis / Q000235:genetics*; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D009367:Neoplasm Staging; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000096:biosynthesis; D015854:Up-Regulation
D004268:DNA-Binding Proteins; D005819:Genetic Markers; C116115:MYCBP protein, human; D014157:Transcription Factors