No abstract

Myc is an oncogenic transcription factor frequently dysregulated in human cancer. To identify pathways supporting the Myc oncogenic program, we employed a genome-wide RNAi screen for Myc-synthetic-lethal genes and uncovered a role for the SUMO-activating-enzyme (SAE1/2). Loss of SAE1/2 enzymatic activity drives synthetic lethality with Myc. Inactivation of SAE2 leads to mitotic catastrophe and cell death selectively upon Myc hyper-activation. Mechanistically, SAE2 inhibition switches a transcriptional subprogram of Myc from activated to repressed. A subset of these SUMOylation-dependent-Myc-switchers (SMS genes) is required for mitotic spindle function and to support the Myc oncogenic program. SAE2 is required for Myc-dependent tumor growth, and patient survival significantly correlates with SAE1/SAE2 levels in Myc-high tumors. These studies reveal a mitotic vulnerability of Myc-driven cancers, demonstrate that inhibiting sumoylation impairs Myc-dependent tumorigenesis, and suggest inhibiting SUMOylation may have therapeutic benefits for patients with Myc-driven cancer.

Several lines of evidence indicate that the nuclear receptor corepressor (N-CoR) complex imposes ligand dependence on transcriptional activation by the retinoic acid receptor and mediates the inhibitory effects of estrogen receptor antagonists, such as tamoxifen, suppressing a constitutive N-terminal, Creb-binding protein͞coactivator complex-dependent activation domain. Functional interactions between specific receptors and N-CoR or SMRT corepressor complexes are regulated, positively or negatively, by diverse signal transduction pathways. Decreased levels of N-CoR correlate with the acquisition of tamoxifen resistance in a mouse model system for human breast cancer. Our data suggest that N-CoR-and SMRT-containing complexes act as rate-limiting components in the actions of specific nuclear receptors, and that their actions are regulated by multiple signal transduction pathways.Nuclear receptors are structurally related, ligand-activated regulators of a complex array of genes involved in cell proliferation, differentiation, morphogenesis, and homeostasis (1, 2). In the absence of ligand, several nuclear receptors associate with a nuclear receptor corepressor (N-CoR) (3-6) or the related factor SMRT (silencing mediator of retinoid and thyroid receptors) (7) to mediate repression. Their regulatory function is further modulated by both physiologic and pharmacologic ligands and by the actions of various signal transduction pathways that result in ligand-independent gene activation of diverse nuclear receptor family members (8)(9)(10).N-CoR and SMRT appear to be components of cellular complexes (4, 11, 12) containing histone deacetylases (HDACs) (13, 14) and homologs of the yeast repressor Sin3 (15, 16), which are recruited to DNA via targeting by diverse DNA-binding, site-specific transcription factors (reviewed in refs. 17 and 18). Conversely, transcriptional activation by nuclear hormone receptors requires the ligand-dependent association of a coactivator complex that includes a family of nuclear receptor coactivators (NCoAs) (19-23) and also includes the histone acetylases Creb-binding protein (CBP)͞ p300 (24-28) and P͞CAF (29,50).The development of inhibitory ligands for the nuclear receptors has yielded important therapeutic treatments, among them the use of tamoxifen for endocrine therapy of breast cancer (reviewed in refs. 10 and 30). However, in certain tissues such as uterus and bone, and after long-term treatment in patients with breast cancer, tamoxifen exhibits unexplained partial agonistic activity (31). Various agents that raise intracellular cAMP levels or stimulate the ras͞MAP kinase pathway can similarly cause estrogen receptor (ER) activation in the presence of tamoxifen or the absence of any activating ligand (9,(32)(33)(34)(35). In this manuscript we show that diverse molecular strategies regulate the association of N-CoR-or SMRT-containing complexes with specific nuclear receptors, including the nature of the ligand, the levels of available N-CoR͞SMRT, and the action of diverse protein ki...

Summary Breast cancer bone micrometastases can remain asymptomatic for years before progressing into overt lesions. The biology of this process, including the microenvironment niche and supporting pathways, is unclear. We find that bone micrometastases predominantly reside in a niche that exhibits features of osteogenesis. Niche interactions are mediated by heterotypic adherens junctions (hAJs) involving cancer-derived E-cadherin and osteogenic N-cadherin, the disruption of which abolishes niche-conferred advantages. We further elucidate that hAJ activates the mTOR pathway in cancer cells, which drives the progression from single cells to micrometastases. Human datasets analyses support the roles of AJ and the mTOR pathway in bone colonization. Our study illuminates the initiation of bone colonization, and provides potential therapeutic targets to block progression toward osteolytic metastases. Significance In advanced stages, breast cancer bone metastases are driven by paracrine crosstalk among cancer cells, osteoblasts, and osteoclasts, which constitute a vicious osteolytic cycle. Current therapies targeting this process limit tumor progression, but do not improve patient survival. On the other hand, bone micrometastases may remain indolent for years before activating the vicious cycle, providing a therapeutic opportunity to prevent macrometastases. Here, we show that bone colonization is initiated in a microenvironment niche exhibiting active osteogenesis. Cancer and osteogenic cells form heterotypic adherens junctions, which enhance mTOR activity and drive early-stage bone colonization prior to osteolysis. These results reveal a strong connection between osteogenesis and micrometastasis and suggest potential therapeutic targets to prevent bone macrometastases.