Cellular and Molecular Correlates in Human Breast Tumor Progression.
Snyder, R.D.*, Richmond, R.E.**, Carter, H.W.*, Pullman, J.L.*, Carter,
J.H.* *Wood Hudson Cancer Research Laboratory, 931 Isabella St., Newport,
KY, 41071 and **Northern Kentucky University, Highland Heights, KY, 41099
ABSTRACT
Poor prognosis associated with advanced stages of breast cancer mandate
that the molecular events associated with disease progression be better
understood and that appropriate early markers for this progression be discovered
and correlated with clinical outcome. While several genetic changes have
been identified as contributing to neoplastic progression in breast cancer,
their exact role in the pathophysiology of breast cancer remains to be determined.
In this study we examined histologic sections of 103 formalin-fixed paraffin
embedded archival breast tissues and carcinomas (CA) for expression of the
p39 transcription-activating protein of c-jun and the p53 oncoprotein of
c-fos, the mutated p53 tumor suppressor gene, and transforming growth factor
beta (TGF-B1) by immunohistochemical techniques. Cells undergoing apoptosis
were visualized by a terminal transferase-mediated in situ end-labeling
(TUNEL) assay. Estrogen receptor (ER) status was determined by the dextran-coated
charcoal method. Expression of c-jun and c-fos was found in 100% of normal
breast specimens. Only 62% of the breast CA expressed c-jun and 77% expressed
c-fos. Conversely, the p53 was expressed in 58% of the CA and in none of
the normal breast specimens. TGF-B1 was expressed in both epithelium and
stroma of most normal breast (90%) but only in 67% of CA. We find that breast
CA can be divided into two classes with respect to apoptosis: those possessing
few, if any apoptotic cells; and those with many apoptotic cells. Interestingly,
80% of tumors with a high apoptotic fraction are ER- and 69% of tumors with
a low apoptotic fraction are ER+. These studies are the first to provide
data directly correlating apoptotic fraction with ER status and expression
of oncogene/growth factor expression.
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