Pregnancy-associated breast
cancers (
PABC) generally present at advanced stages and have a poor prognosis. The reasons are unclear but we hypothesized that the continuous high levels of
estrogens and
progesterone were involved. We have now carried out a detailed analysis of
PABC compared to
tumors of age-matched nonpregnant (non-
PABC) women. Malignant epithelia and
tumor-associated stroma of
PABC and non-
PABC were isolated by
laser capture microdissection and gene expression profiled. Additionally, normal breast epithelia and stroma adjacent to the two
tumor types were analyzed. Lastly, subsets of previously identified E- and P-regulated genes were defined in all tissues. We find that
PABC signatures cluster with established
breast cancer subtypes. Major
hormone-regulated genes whose expression correlated with epithelia of
PABC dealt with regulation of cell proliferation, metabolism, and
tumor aggressiveness, including genes used to predict
tumor recurrence. Compared to normal epithelia, a significant number of genes associated with cell cycle processes were enriched in
PABC, many of which are
hormone regulated. Thus, compared to normal epithelia, many of the genes that were differentially expressed in epithelia of
PABC were distinct from those differentially expressed in non-
PABC. With regard to the tumor microenvironment, immune-related genes were enriched in
tumor-associated stroma of
PABC. Compared to normal stroma,
PABC-associated stroma overexpressed immune response genes, while genes involved in angiogenesis and extracellular matrix deposition were more commonly downregulated. This suggests that the heightened aggressiveness of
PABC may involve a predisposition to
metastasis through extracellular matrix degradation, plus angiogenesis independence. Moreover, genes encoding cell proliferative factors, signaling,
immunomodulators and cell death, were
hormone regulated in stroma. In sum, these analyses demonstrate complex patterns of enrichment and hormonal regulation of genes in
PABC and suggest that it may have a distinct
biological nature.