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...

Progesterone regulates diverse biological effects in a broad range of tissues, mostly by interaction with the classical progesterone receptor (PR), a member of the nuclear receptor superfamily of ligand-dependent transcription factors. Particularly in the mammary gland, progesterone plays a key role in the control of cell proliferation and differentiation (31 and references within). Accumulated evidence also indicates that progestins are involved in controlling mammary gland tumorigenesis, both in women and in animal models (6,8,15,21,24,26,31,32,48). Although the mechanisms by which progestins stimulate growth of breast cancer cells have not been completely deciphered, several lines of evidence (6, 26, 33), including our own work (3,4,25,44), have shown that convergence between progestins and growth factor (GF) signaling pathways mediates proliferative effects of progestins in mammary tumor cells.In addition to their direct transcriptional effects, rapid or nongenomic biological effects of progestins have been described in several species, including fish, amphibian, and mammalian (27). Whether the recently cloned membrane PR from humans and other vertebrates (59) is involved in mediating nongenomic progestin effects in mammalians remains to be elucidated. Nongenomic effects of progestins in breast cancer cells have been unraveled by startling reports from Auricchio and coworkers (5,13,33), who demonstrated that progestin treatment of human breast cancer T47D cells activates the signal-transducing c-Src/p21 ras /MAPK pathway, which results in cell proliferation (5,13,33). Progestin activation of the c-Src/p21 ras /MAPK pathway has also been described by Edwards and coworkers (6), who further explored mechanisms involved in progestin modulation of c-Src activity.Over the last years, a unique family of proteins, the signal transducers and activators of transcription (Stats), was found to be involved in cross talks with both steroid hormones and

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