Normal epithelial cells require matrix attachment for survival and the ability of tumour cells to survive outside their natural extracellular matrix (ECM) niches is dependent on acquisition of anchorage independence1. While apoptosis is the most rapid mechanism for eliminating cells lacking appropriate ECM attachment2, recent reports suggest that non-apoptotic death processes prevent survival when apoptosis is inhibited in matrix-deprived cells3 , 4. Here we demonstrate that detachment of mammary epithelial cells from ECM causes an ATP deficiency due to loss of glucose transport. Overexpression of ErbB2 rescues the ATP deficiency by restoring glucose uptake through stabilization of EGFR and PI(3)K activation and this rescue is dependent on glucose-stimulated flux through the antioxidant-generating pentose phosphate pathway (PPP). Interestingly, we found that the ATP deficiency could be rescued by antioxidant treatment without rescue of glucose uptake. This rescue was found to be dependent on stimulation of fatty acid oxidation (FAO), which is inhibited by detachment-induced reactive oxygen species (ROS). The significance of these findings was supported by evidence of an elevation in ROS in matrix-deprived cells in the luminal space of mammary acini and that antioxidants facilitate the survival of these cells and enhance anchorageindependent colony formation. These results reveal both the importance of matrix attachment in regulating metabolic activity and an unanticipated mechanism for cell survival in altered matrix environments through antioxidant restoration of ATP generation.Epithelial cells are dependent on interactions with specific extracellular matrix (ECM) components for survival, proliferation, and differentiation functions 5 . Loss of matrix attachment of cultured epithelial cells activates a caspase-mediated apoptotic program known as anoikis2. In glandular cancers, like breast cancer, tumour cells are displaced from their * To whom correspondence should be addressed: Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, Phone: 617-432-3974, Fax: 617-432-3969, joan_brugge@hms.harvard.edu. 4 Present address: Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556 † These authors contributed equally to this work.Supplementary information is linked to the online version of the paper at www.nature.com/nature. A figure summarising the main result of this paper ( Supplementary Fig. 1) is included in the supplementary information.Author Contributions Z.T.S. and J.S.B. were responsible for the overall study design. Z.T.S., A.R.G., H.Y.I., and S.G. conducted experiments. L.S. and Z.J. conducted the experiments measuring native fluorescence of NAD(P)H in 3D cell culture. Z.G.-H. and P.P. designed the fatty acid oxidation studies and Z.T.S. and Z.G.-H. conducted the fatty acid oxidation assays. Z.T.S. and J.S.B. drafted the manuscript and all other authors made revisions. Author InformationReprints and permissions information is available...

Purpose Cure rates for localized high-risk prostate cancers (PCa) and some intermediate-risk PCa are frequently suboptimal with local therapy. Outcomes are improved by concomitant androgen-deprivation therapy (ADT) with radiation therapy, but not by concomitant ADT with surgery. Luteinizing hormone–releasing hormone agonist (LHRHa; leuprolide acetate) does not reduce serum androgens as effectively as abiraterone acetate (AA), a prodrug of abiraterone, a CYP17 inhibitor that lowers serum testosterone (< 1 ng/dL) and improves survival in metastatic PCa. The possibility that greater androgen suppression in patients with localized high-risk PCa will result in improved clinical outcomes makes paramount the reassessment of neoadjuvant ADT with more robust androgen suppression. Patients and Methods A neoadjuvant randomized phase II trial of LHRHa with AA was conducted in patients with localized high-risk PCa (N = 58). For the first 12 weeks, patients were randomly assigned to LHRHa versus LHRHa plus AA. After a research prostate biopsy, all patients received 12 additional weeks of LHRHa plus AA followed by prostatectomy. Results The levels of intraprostatic androgens from 12-week prostate biopsies, including the primary end point (dihydrotestosterone/testosterone), were significantly lower (dehydroepiandrosterone, Δ4-androstene-3,17-dione, dihydrotestosterone, all P < .001; testosterone, P < .05) with LHRHa plus AA compared with LHRHa alone. Prostatectomy pathologic staging demonstrated a low incidence of complete responses and minimal residual disease, with residual T3- or lymph node–positive disease in the majority. Conclusion LHRHa plus AA treatment suppresses tissue androgens more effectively than LHRHa alone. Intensive intratumoral androgen suppression with LHRHa plus AA before prostatectomy for localized high-risk PCa may reduce tumor burden.

Background-Understanding the mechanisms driving disease progression is fundamental to identifying new therapeutic targets for the treatment of men with metastatic castration-resistant prostate cancer (mCRPC). Due to the prevalence of bone metastases in mCRPC, obtaining sufficient tumor tissue for analysis has historically been a challenge. In this exploratory analysis, we evaluated imaging, procedural, and clinical variables associated with tumor yield on imageguided bone biopsy in men with mCRPC.