Progesterone receptor (PR) and ErbB-2 bidirectional cross talk participates in breast cancer development. Here, we identified a new mechanism of the PR and ErbB-2 interaction involving the PR induction of ErbB-2 nuclear translocation and the assembly of a transcriptional complex in which ErbB-2 acts as a coactivator of Stat3. We also highlighted that the function of ErbB-2 as a Stat3 coactivator drives progestin-induced cyclin D1 promoter activation. Notably, PR is also recruited together with Stat3 and ErbB-2 to the cyclin D1 promoter, unraveling a new and unexpected nonclassical PR genomic mechanism. The assembly of the nuclear Stat3/ErbB-2 transcriptional complex plays a key role in the proliferation of breast tumors with functional PR and ErbB-2. Our findings reveal a novel therapeutic intervention for PR-and ErbB-2-positive breast tumors via the specific blockage of ErbB-2 nuclear translocation.Progesterone receptor (PR) and the ErbB family of receptor tyrosine kinases are major players in the breast cancer scenario. In its classical mechanism of action, PR acts as a ligandinduced transcription factor. Upon progestin binding, PR translocates to the nucleus and binds to specific progesterone response elements (PREs) in the promoter of target genes (31). In addition to its direct transcriptional effects, PR activates signal transduction pathways in breast cancer cells through a rapid or nongenomic mechanism (5, 22). On the other hand, the ErbB family of membrane receptor tyrosine kinases is composed of four members: epidermal growth factor (EGF) receptor (EGF-R) (ErbB-1), ErbB-2, ErbB-3, and ErbB-4. ErbB ligands include all isoforms of heregulins (HRGs), which bind to ErbB-3 and ErbB-4 and recognize EGF-R and ErbB-2 as coreceptors, and EGF, which binds to EGF-R (33). Upon ligand binding, ErbBs dimerize, and their intrinsic tyrosine kinase activity is stimulated, which leads to the activation of signal transduction pathways that mediate ErbB's proliferative effects. Although ErbB-2 is an orphan receptor, it participates in an extensive network of ligandinduced formation of ErbB dimers. Notably, this dogma of the ErbB-2 mechanism of action has been challenged by the most exciting findings of Wang and coworkers, demonstrating that ErbB-2 migrates to the nuclear compartment, where it binds DNA at specific sequences, which those authors named HER-2-associated sequences (HASs) (35). Through this function as a transcription factor, ErbB-2 modulates the expression of the cyclooxygenase-2 (COX-2) gene (35). The association of ErbB-2 with the COX-2 promoter was detected in breast cancer cell lines overexpressing ErbB-2 as well as in ErbB-2-positive human primary breast tumors (35).Accumulating findings, including ours, have proven the presence of bidirectional interactions between PR and ErbB signaling pathways in breast cancer. On the one hand, we showed that PR activates the HRG/ErbB-2 pathway (2). On the other hand, we found that HRG induces PR transcriptional activation in breast tumors through a mechanism that req...

Key Points• We elucidate a molecular mechanism by which thyroid hormones sustain TCL survival.• We demonstrate that the membrane receptor of THs, integrin avb3, constitutes a potential target for TCL.The interaction of lymphoid tumor cells with components of the extracellular matrix via integrin avb3 allows tumor survival and growth. This integrin was demonstrated to be the membrane receptor for thyroid hormones (THs) in several tissues. We found that THs, acting as soluble integrin avb3 ligands, activated growth-related signaling pathways in T-cell lymphomas (TCLs). Specifically, TH-activated avb3 integrin signaling promoted TCL proliferation and angiogenesis, in part, via the upregulation of vascular endothelial growth factor (VEGF). Consequently, genetic or pharmacologic inhibition of integrin avb3 decreased VEGF production and induced TCL cell death in vitro and in human xenograft models. In sum, we show that integrin avb3 transduces prosurvival signals into TCL nuclei, suggesting a novel mechanism for the endocrine modulation of TCL pathophysiology. Targeting this mechanism could constitute an effective and potentially low-toxicity chemotherapy-free treatment of TCL patients. (Blood. 2015;125(5):841-851)

Peripheral T-cell lymphomas (PTCL) are aggressive diseases with poor response to chemotherapy and dismal survival. Identification of effective strategies to target PTCL biology represents an urgent need. Here we report that PTCL are sensitive to transcription-targeting drugs, and, in particular, to THZ1, a covalent inhibitor of cyclin-dependent kinase 7 (CDK7). The STAT-signalling pathway is highly vulnerable to THZ1 even in PTCL cells that carry the activating STAT3 mutation Y640F. In mutant cells, CDK7 inhibition decreases STAT3 chromatin binding and expression of highly transcribed target genes like MYC, PIM1, MCL1, CD30, IL2RA, CDC25A and IL4R. In surviving cells, THZ1 decreases the expression of STAT-regulated anti-apoptotic BH3 family members MCL1 and BCL-XL sensitizing PTCL cells to BH3 mimetic drugs. Accordingly, the combination of THZ1 and the BH3 mimetic obatoclax improves lymphoma growth control in a primary PTCL ex vivo culture and in two STAT3-mutant PTCL xenografts, delineating a potential targeted agent-based therapeutic option for these patients.