Crosstalk between STAT5 activation and PI3K/AKT functions in normal and transformed mammary epithelial cells

Abstract

Summary Janus kinases (JAKs) and signal transducers and activators of transcription (STATs) have been shown to function downstream of several peptide hormones and cytokines that are required for postnatal development and secretory function of the mammary gland. As part of an extended network, these signal transducers can engage in crosstalk with other pathways to facilitate synergistic, and sometimes antagonistic, actions of different growth factors. Specifically, signaling through the JAK2/STAT5 cascade has been demonstrated to be indispensable for the specification, proliferation, differentiation, and survival of secretory mammary epithelial cells. Following a concise description of major cellular programs in mammary gland development and the role of growth factors that rely on JAK/STAT signaling to orchestrate these programs, this review highlights the significance of active STAT5 and its crosstalk with the PI3 kinase and AKT1 for mediating the proliferation of alveolar progenitors and survival of their functionally differentiated descendants in the mammary gland. Based on its ability to provide self-sufficiency in growth signals that are also capable of overriding intrinsic cell death programs, persistently active STAT5 can serve as a potent oncoprotein that contributes to the genesis of breast cancer. Recent experimental evidence demonstrated that, similar to normal developmental programs, oncogenic functions of STAT5 rely on molecular crosstalk with PI3K/AKT signaling for the initiation, and in some instances the progression, of breast cancer. The multitude by which STATs can interact with individual mediators of the PI3K/AKT signaling cascade may provide novel avenues for targeting signaling nodes within molecular networks that are crucial for the survival of cancer cells.

Spontaneous aggressive ERα+ mammary tumor model is driven by Kras activation

“…Consistently, tumors that arise in NRL-PRL females lose dependence on JAK2 signaling with disease progression (Sakamoto et al, 2010) , whereas mammary tumors in Stat1 -deficient mice remain dependent on JAK2 (Chan et al, 2014) . Together, these data are congruent with a model whereby JAK2/STAT5A signals promote early tumorigenesis, but their ongoing activity supports well-differentiated less aggressive luminal cancers which are more likely to respond to anti-estrogen therapies (Peck et al, 2012;Rädler et al, 2017) .…”

Janus Kinase 1 Plays a Critical Role in Mammary Cancer Progression

“…A review of the recent literature in the field of cancer research, however, shows that JAK2 is now being perceived as the primary therapeutic target to block the oncogenic activation of STATs, in particular STAT3 (Rädler et al, 2017). This view appears to have emerged from the experimental use of pharmacological agents that are marketed as ‘‘JAK2 inhibitors’’ despite their known off-target effects on other JAKs.…”

“…In contrast to the pro-survival function of JAK2 and STAT5, which promote the earliest steps of neoplastic transformation (for references, see Rädler et al, 2017), signaling through JAK1 seems to be dispensable for ERBB2-induced mammary cancer initiation. Similar to MMTV-Neu transgenic females with a mammary gland-specific knockout of STAT3 (Ranger et al, 2009), loss of JAK1 had no effect on tumor-free survival but blocked dissemination of ERBB2-driven mammary tumor cells to distant sites.…”

“…More recent evidence suggests that the hyper-phosphorylation of STAT3 is likely the result of elevated and cancer cell-specific production of IL-6 and downstream activation of gp130/JAK complexes in response to RTK signaling (Berishaj et al, 2007). In preneoplastic and transformed epithelial cells, the pro-apoptotic functions of STAT3 can be effectively neutralized by sustained activation of survival factors; in particular, STAT5, phosphatidylinositol 3-kinase (PI3K) and AKT1 (for references, see Rädler et al, 2017). Under these disease-specific conditions, constitutively active STAT3 may still promote other facets of tissue remodeling within a malignant tumor, such as the enzymatically controlled detachment of cancer cells from the basement membrane.…”

Genetic and epigenetic modifications of HPDL and SOX17 associated with breast cancer prognosis: a study based on The Cancer Genome Atlas

“…Previous studies have found that activation of the JAK/STAT pathway is common in triple-negative BRCA, which can affect the expression of genes controlling immune signals. Dysregulated JAK/STAT signaling has been implicated in BRCA metastasis, associated with high risk of recurrence [39][40][41]. The Wnt signaling pathway plays a crucial role in early embryonic development, organ formation, tissue regeneration, and other physiological processes, often involving stem cell control, which may induce cancer if a key protein is mutated [42].…”