Signal transducers and activators of transcription (STATs) in breast cancer

STAT proteins are activated during mammary gland development and in a variety of tumors. STAT5 is required for alveolar differentiation and the response to lactogenic hormones. In contrast to tumors of the hematopoietic system, where STAT5 has been implicated in tumor formation and progression, in mammary carcinomas STAT5 activation and expression of the STAT5 target gene SOCS2 are linked to good prognosis. STAT3 is a key factor in the initiation of mammary gland involution, however its role in breast cancer remains unclear. STAT1 is considered to act as an anti-oncogene and linked to cell cycle arrest and apoptosis. Furthermore it is considered to be a key factor in tumor immunosurveillance and the response to chemotherapeutics. By studying STAT1 DNA binding activity and tyrosine phosphorylation as markers for STAT1 activation, we have observed a link between STAT1 activity and good prognosis in primary human breast cancer. One hypothesis to explain these findings is that impaired STAT1 function can promote resistance to chemotherapeutics. A causal relationship between STAT1 and resistance to chemotherapy was tested in an animal model for erbB2 positive breast cancer, the MMTVneu (N) tumor mice, which develop adenocarcinomas. STAT1 proficient and deficient animals in FVB/N background were generated. Tumor formation and response to the chemotherapeutic agent doxorubicin, which is frequently used in the therapy of erbB2 positive human breast cancer, was investigated. We observe a shorter tumor latency in STAT1 deficient mice. Furthermore, STAT1 deficient mice exhibited an impaired response to doxorubicin treatment in vivo. In accordance, the effect of doxorubicin on activation of p53, induction of apoptosis, and formation of DNA strand breaks as judged by gH2AX phosphorylation was diminished in tumor explant cultures derived from STAT1 deficient mice. Our experiments indicate that in erbB2 positive mammary carcinoma, loss of STAT1 leads to an accelerated tumor development and to resistance against doxorubicin treatment, suggesting that the determination of the STAT1 activation status in breast cancer can serve as an important parameter to predict response to chemotherapy.