STAT5 influences differentiation, survival, and proliferation through alterations in cellular gene expression. After activation by tyrosine phosphorylation (P), STAT5A and STAT5B form homodimers and heterodimers that move into the nucleus, where they can act as transcription factors to influence gene expression. STAT5, signal transducer and activator of transcription 5.

Signaling pathways and proteins that increase or decrease STAT5 signaling in normal mammary epithelial cells. Research to date has identified several factors that contribute to higher levels of STAT5 activation or, conversely, reduce activation levels in normal mammary epithelial cells. E74-like factor 5 (ets domain transcription factor) (ELF5) acts in the PRL/JAK2 signaling pathway to increase levels of STAT5 activation in normal mammary epithelial cells. Other signaling pathway components that increase STAT5 activation are EGF, ErbB2, transforming growth factor-alpha (TGF-α), estrogen acting with the progesterone pathway acting downstream, GH/JAK2, IGF, and c-Src. The TGF-β signaling pathway can decrease STAT5 activation levels. Cellular proteins that contribute to increased STAT5 activation include PI 3-kinase enhancer A (PIKE-A), serine/threonine protein kinase Akt 1 (AKT-1), p21-activated kinase 1 (Pak1), the phosphotyrosine phosphatase Shp2, beta-integrin, and dystroglycan. Cellular proteins that have been shown to decrease STAT5 activation levels include caveolin-1 and suppressor of cytokine signaling 3 (SOCS-3). c-Src, human cellular-Src; EGF, epidermal growth factor; ErbB4, v-erb-b2 erythroblastic leukemia viral oncogene homolog 4, neuro/glioblastoma-derived oncogene homolog (avian); GH, growth hormone; IGF, insulin growth factor; JAK2, Janus kinase 2; PRL, prolactin; Shp2, Src homology region 2 domain-containing phosphatase-2; STAT5, signal transducer and activator of transcription 5.

STAT5 is required for differentiation of luminal progenitor cells into alveolar cells. STAT5 activation mediates alveolar cell fate commitment and proliferation that leads to lactational differentiation. Mammary stem cells give rise to progenitor cells that differentiate into ductal or luminal progenitor cells. ELF5 induces differentiation of luminal progenitor cells into alveolar cells downstream of prolactin signaling. Cell types illustrated in pink exhibit STAT5 activation. ELF5, E74-like factor 5 (ets domain transcription factor); PRL, prolactin; STAT5, signal transducer and activator of transcription 5.

STAT5 expression in human breast cancer is generally associated with increased differentiation. In human breast cancer tissue, STAT5 expression has been reproducibly associated with increased differentiation and a better prognosis and response to endocrine therapy. Experiments that alter STAT5 expression levels in breast cancer cell lines revealed a link between the presence of STAT5 and increased differentiation in BT-20, T47D, and MDA-MB-468 breast cancer cell lines. Increased cell motility, invasiveness, and migration are behaviors that can be found in association with decreased differentiation. In MCF-7 andT47D cells lines, STAT5 inhibits motility, and in the T47D cell line loss of STAT5 increases invasiveness and this is consistent with the correlation between STAT5 and increased differentiation. However, in MDA-MB-231 and BT-549, loss of STAT5 actually inhibits migration. Increased sensitivity to therapy is considered a good prognostic sign, and in the MDA-MB-468 cell line, STAT5 is correlated with increased sensitivity to paclitaxel and vinorelbine. However, in SKBR3, MCF-7, and T47D cell lines, experiments have correlated the presence of STAT5 with increased cell survival and, in T47D cells, resistance to tamoxifen and, in SKBR3 cells, a decreased response to trastuzumab. In SKBR3 and MD-MBA-231 cells, loss of STAT5 is actually correlated with growth inhibition. These sometimes consistent and sometimes conflicting results in different breast cancer cell lines indicate that the relative impact of STAT5 on cell differentiation, survival, and proliferation can be cell line-specific. BCL6 gene expression and activating protein-1 (AP-1) signaling are reduced by increased STAT5 signaling and increased by reduced STAT5 signaling. Identified downstream STAT5 genes in breast cancer cells include heat shock protein 90-A (HSP90A), insulin growth factor (IGF), and cyclin D1. BCL6, proto-oncogene B-cell chronic lymphocytic leukemia/lymphoma 6; STAT5, signal transducer and activator of transcription 5.

STAT5 can be activated by diverse and sometimes interacting signaling pathways in mammary epithelial cells. Prolactin (PRL) signaling networks dominate in STAT5 activation in normal mammary gland development with contributions from growth hormone (GH), insulin growth factor (IGF), estrogen, epidermal growth factor (EGF), and ErbB4 signaling. PRL and GH work predominantly through their respective receptors prolactin receptor (PR) and growth hormone receptor (GHR) through Janus kinase 2 (JAK2) and are key mediators of pregnancy-induced mammary gland development. Estrogen and EGF acting through respective receptors estrogen receptor-alpha (ERα) and EGF receptor (EGFR) initiate pubertal mammary gland development and contribute to pregnancy-induced development. They can interact through human cellular-Src (c-Src) pathways. Transforming growth factor-alpha (TGF-α) is the second ligand from the EGF family to be shown to influence STAT5 activation levels in normal and cancer cells. IGF signaling through insulin growth factor-related receptors (IGFRs) may also include c-Src and, under some circumstances, JAK2 in both puberty- and pregnancy-induced development. The contribution of ErbB4 to STAT5 signaling is most prominent during lactation. In breast cancer, EGF and estrogen pathways acting through c-Src can drive proliferation and survival. JAK1 has been shown to increase PR/JAK2 activation in some settings. When the erythropoietin receptor (EPOR) is expressed in breast cancer cells and erythropoietin (EPO) is present, they can signal through JAK2 to STAT5 to promote resistance to trastuzumab therapy. ErbB4, v-erb-b2 erythroblastic leukemia viral oncogene homolog 4, neuro/glioblastoma-derived oncogene homolog (avian); STAT5, signal transducer and activator of transcription 5.

Signaling pathways and proteins that can increase or decrease STAT5 signaling in breast cancer cells. Research to date has identified several factors that can contribute to higher levels of STAT5 activation or, conversely, reduce activation levels in breast cancer cells. As in normal mammary epithelial cells, PRL/JAK2, c-Src, EGF/EGFR, ErbB4, TGF-α, estrogen and progesterone, and IGF pathways can increase STAT5 activation. In breast cancer cells, EPO/EPOR and HOXA1 also have been shown to increase STAT5 signaling. Two cellular proteins shown to increase STAT5 activation in breast cancer cells are breast tumor kinase (Brk) and transcription factor proto-oncogene v-Myb myeloblastosis viral oncogene homolog (avian) (c-Myb). As in normal mammary epithelial cells, caveolin-1 and SOCS-3 can downregulate STAT5 activation; however, in breast cancer cells, PTPN9 (protein tyrosine phosphatase, non-receptor type 9) also has been shown to downregulate STAT5 signaling. c-Src, human cellular-Src; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; EPO, erythropoietin; EPOR, erythropoietin receptor; ErbB4, v-erb-b2 erythroblastic leukemia viral oncogene homolog 4, neuro/glioblastoma-derived oncogene homolog (avian); HOXA1, homeobox A1; IGF, insulin growth factor; JAK2, Janus kinase 2; PRL, prolactin; SOCS-3, suppressor of cytokine signaling 3; STAT5, signal transducer and activator of transcription 5; TGF-α, transforming growth factor-alpha.

Increased STAT5 initiates cancer and decreased STAT5 diminishes cancer promotion in genetically engineered mouse models. Increased levels of STAT5 expression and/or activation either directly by transgene-mediated STAT5 overexpression or indirectly through genetically engineered loss of caveolin-1 leads to initiation, promotion, and progression to mammary cancer. Decreased levels of STAT5 expression reduce cancer promotion initiated by transgene-mediated overexpression of prolactin, transforming growth factor-alpha (TGF-α), and estrogen receptor-alpha (ERα) as well as mammary-targeted simian virus 40 T antigen. STAT5, signal transducer and activator of transcription 5.