EGFR dependent expression of STAT3 (but not STAT1) in breast cancer

STAT proteins constitute a family of transcription factors whose activation by cytokine and non-cytokine receptors leads to tyrosine phosphorylation, dimerization and translocation from the cytoplasm to the nucleus. In the nu cleus they activate the transcription of specific genes by binding to conse nsus DNA elements. STATs 1 and 3 can be activated by both cytokine and non- cytokine receptors, and bind as homodimers or heterodimers to viral simian sarcoma virus (sis)-inducible elements such as that found in the c-fos prom oter. Activation of c-Src and EGF receptor tyrosine kinases is associated w ith progression of breast cancer. Both these events lead to activation of S TAT proteins, Ste kinases activate STAT3 dependent transcription in mammary epithelial cells and EGF receptor activation can lead to activation of STA Ts 1 and 3. STAT3 activation has been demonstrated to have a role in oncoge nesis and increasingly, activated STAT proteins are found to be activated i n human cancer. In this study we describe detailed immunohistochemical anal ysis of nuclear and cytoplasmic STATs 1 and 3 expression in primary breast carcinomas and correlate this with EGFR, HER2, p53, ER, PR, p21/waf1, Bcl-X -L and Ki-67 expression. We also compared expression between normal and tum or tissue. We report here a highly significant correlation between nuclear STAT3 expression and breast cancers compared to normal tissue. We also repo rt a very strong correlation between nuclear STAT3 and EGFR expression in b reast cancers. These data clearly demonstrate a strong association between STAT3 activation and breast tumorigenesis and strengthen the assertion that STAT3 activationmay play an important role in the tumorigenic conversion o f breast tissue mediated by tyrosine kinase signaling pathways.