STAT family of transcription factors in breast cancer: Pathogenesis and therapeutic opportunities and challenges

Abstract

Breast cancer is the most commonly diagnosed cancer and second-leading cause of cancer deaths in women. Breast cancer stem cells (BCSCs) promote metastasis and therapeutic resistance contributing to tumor relapse. Through activating genes important for BCSCs, transcription factors contribute to breast cancer metastasis and therapeutic resistance, including the signal transducer and activator of transcription (STAT) family of transcription factors. The STAT family consists of six major isoforms, STAT1, STAT2, STAT3, STAT4, STAT5, and STAT6. Canonical STAT signaling is activated by the binding of an extracellular ligand to a cell-surface receptor followed by STAT phosphorylation, leading to STAT nuclear translocation and transactivation of target genes. It is important to note that STAT transcription factors exhibit diverse effects in breast cancer; some are either pro- or anti-tumorigenic while others maintain dual, context-dependent roles. Among the STAT transcription factors, STAT3 is the most widely studied STAT protein in breast cancer for its critical roles in promoting BCSCs, breast cancer cell proliferation, invasion, angiogenesis, metastasis, and immune evasion. Consequently, there have been substantial efforts in developing cancer therapeutics to target breast cancer with dysregulated STAT3 signaling. In this comprehensive review, we will summarize the diverse roles that each STAT family member plays in breast cancer pathobiology, as well as, the opportunities and challenges in pharmacologically targeting STAT proteins and their upstream activators in the context of breast cancer treatment.

Keywords: Breast cancer; Breast cancer stem cells (BCSCs); Breast cancer therapeutics; STAT inhibitors; Signal transducer and activator of transcription (STAT).

Fig. 1.. STAT structure.

The signal transducer and activator of transcription (STAT) family members are ~740–900 amino acids in length and maintain relatively conserved regions in their structures. Each STAT protein contains these functionally conserved domains: 1) N-terminal domain (NTD) capped with NH2, 2) coiled-coiled domain (CCD), 3) DNA-binding domain (DBD), 4) linker domain (LD), 5) SRC homology 2 domain (SH2), 6) tyrosine phosphorylation site (pY), and 7) C-terminal transactivation domain (TAD) containing COOH. STAT4 is the shortest STAT protein (748), while STAT2 is the longest (851). Additionally, there is another conserved phospho-serine residue in the TAD of STAT1, STAT3, STAT5a, STAT5b, and STAT6.

Fig. 2.

Canonical STAT pathway activation. STAT proteins are activated by a myriad of cytokines or growth factors (i.e. ligands), which bind to extracellular domains on cell-surface receptors (i.e. receptors) to form ligand-receptor complexes. The canonical IL-6/IL-6Ralpha/STAT3 pathway (left), for example, involves the IL-6 cytokine (ligand) binding to the IL-6Ralpha, which activates gp130 association with IL-6/IL-6Ralpha. Two trimeric IL-6/IL-6Ralpha/STAT3 complexes interact, recruit JAKs, phosphorylate the intracellular domains of gp130, activate STAT3 via phosphorylation, pSTAT3 dimers then translocate to the nucleus where they modulate gene expression of downstream target genes. Additional receptors, such as EGF or FGF receptors (right), retain intrinsic kinase activities and can directly phosphorylate STAT proteins leading to STAT phosphorylation, dimerization, and subsequent translocation to the nucleus. Though there are reports of alternative STAT activation including methods where STAT proteins form dimers without phosphorylation, this pathway describes the most common STAT pathway activation.