Expression of Phospho(p)STAT3 and Phospho(p)STAT5 in Breast Cancer and Correlation with Plasma Prolactin Levels
NA Belsley, LC Collins, MS Rice, S Walker, S Tworoger, DA Frank. Beth Israel Deaconess Medical Center, Boston; Harvard Medical School, Boston; Channing Institute, Boston; Dana-Farber Cancer Institute, Boston
Background: Signal Transducer and Activator of Transcription (STAT) 3 and 5 are transcription factors activated by multiple ligands. In the breast, in response to prolactin, STAT5 promotes proliferation and milk production. STAT3, which is activated by cytokines such as LIF, promotes apoptosis and involution. We examined expression of pSTAT 3 and 5 in breast cancer and in relation to plasma prolactin levels.
Design: Tissue microarrays (TMAs) were constructed from 3,093 breast cancers from women enrolled in the Nurses Health Study. Of these, 443 patients had matching plasma prolactin levels drawn at diagnosis. Immunohistochemical studies with pSTAT3 and 5 were performed on the TMAs. Tissue cores were scored from 0-3 based on intensity and quantity of nuclei staining. Relationships between expression of pSTAT3 or pSTAT5 and clinicopathologic features were examined.
Results: Interpretable tissue cores were available for 309 subjects. Of these, 195 (63%) and 114 tumors (37%) showed negative/weak (0-1) and moderate/strong staining (2-3) respectively for pSTAT3. 178 (58%) and 131 (42%) tumors showed negative/weak and moderate/strong staining respectively for pSTAT5. Thirty four (11%) tumors were in-situ and 275 (89%) tumors were invasive carcinomas. Absence of expression of pSTAT3 was significantly more common in high grade tumors (p=0.04) and in invasive vs. in situ carcinomas (p=0.04). Though not statistically significant, pSTAT3- status also was associated with lymph node involvement and larger tumor size. Among post menopausal women, there was a significant increase in risk of pSTAT3+ and pSTAT5+ breast cancers in women in the top vs. bottom quartile of plasma prolactin levels (RR= 2.0 [95%CI 1.2-3.2] and 2.3 [95%CI 1.3-4.1] respectively). No association was observed between prolactin levels and pSTAT3- or pSTAT5- tumors.
Conclusions: The transcription factor STAT3, which plays a role in cell death and involution of lactating lobules, is activated in breast cancer. Absence of pSTAT3 expression correlates significantly with invasive cancer and higher tumor grade. Our findings suggest that the role of STAT3 in breast cancer mirrors its physiologic role. An association between plasma prolactin and pSTAT3+ and pSTAT5+ tumors is also seen. However, further studies are needed to fully elucidate the interactions of the STATs on breast cancer pathogenesis.
Monday, March 9, 2009 1:00 PM
Poster Session II # 44, Monday Afternoon