Age-specific differences in oncogenic pathway deregulation seen in human breast tumors

PLoS One. 2008 Jan 2;3(1):e1373. doi: 10.1371/journal.pone.0001373.


Purpose: To define the biology driving the aggressive nature of breast cancer arising in young women.

Experimental design: Among 784 patients with early stage breast cancer, using prospectively-defined, age-specific cohorts (young <or=45 years; older >or=65 years), 411 eligible patients (n = 200<or=45 years; n = 211>or=65 years) with clinically-annotated Affymetrix microarray data were identified. GSEA, signatures of oncogenic pathway deregulation and predictors of chemotherapy sensitivity were evaluated within the two age-defined cohorts.

Results: In comparing deregulation of oncogenic pathways between age groups, a higher probability of PI3K (p = 0.006) and Myc (p = 0.03) pathway deregulation was observed in breast tumors arising in younger women. When evaluating unique patterns of pathway deregulation, a low probability of Src and E2F deregulation in tumors of younger women, concurrent with a higher probability of PI3K, Myc, and beta-catenin, conferred a worse prognosis (HR = 4.15). In contrast, a higher probability of Src and E2F pathway activation in tumors of older women, with concurrent low probability of PI3K, Myc and beta-catenin deregulation, was associated with poorer outcome (HR = 2.7). In multivariate analyses, genomic clusters of pathway deregulation illustrate prognostic value.

Conclusion: Results demonstrate that breast cancer arising in young women represents a distinct biologic entity characterized by unique patterns of deregulated signaling pathways that are prognostic, independent of currently available clinico-pathologic variables. These results should enable refinement of targeted treatment strategies in this clinically challenging situation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Age Factors*
  • Aged
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • Cohort Studies
  • Female
  • Humans
  • Middle Aged
  • Oncogenes*