The level of HIF-1 alpha increases as the pathologic stage increases and is higher in poorly differentiated lesions than in the corresponding type of well-differentiated lesions. Increased levels of HIF-1 alpha are associated with increased proliferation and increased expression of ER and VEGF. Thus, increased levels of HIF-1 alpha are potentially associated with more aggressive tumors.

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The multidrug-resistance associated protein MRP is a 180-to 195-kDa membrane protein associated with resistance of human tumor cells to cytotoxic drugs. We have investigated how MRP confers drug resistance in SW-1573 human lung carcinoma cells by generating a subline stably transfected with an expression vector containing MRP cDNA. MRP-overexpressing SW-1573 cells are resistant to doxorubicin, daunorubicin, vincristine, VP-16, colchicine, and rhodamine 123, but not to 4'-(9-acridinylamino)methanesulfon-manisidide or taxol. The intracellular accumulation of drug (daunorubicin, vincristine, (20) and pRc/RSV (Invitrogen). All cDNA fragments used for the assembly of the MRP cDNA were sequenced and the integrity of the MRP cDNA fragment in the resulting expression vectors, pJ3fl-MRP and pRc/RSV-MRP (Fig. 1) Abbreviations: MDR, multidrug resistance (resistant); Pgp, P-glycoprotein; SCLC, small-cell lung cancer; pH;, intracellular pH; m-AMSA, 4'-(9-acridinylamino)methanesulfon-m-anisidide. 8822The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

BACKGROUNDHypoxia‐inducible factor‐1 (HIF‐1) is a transcription factor that plays an important role in tumor growth and metastasis by regulating energy metabolism and inducing angiogenesis to survive cellular hypoxia. Increased levels of HIF‐1α, the O2‐regulated subunit of HIF‐1, were noted during breast carcinogenesis. In this study, the prognostic value of HIF‐1α expression and its correlation with various clinicopathologic variables in patients with invasive breast carcinoma were investigated.METHODSExpression levels of HIF‐1α, HER‐2/neu, estrogen receptor, and progesterone receptor were analyzed in 150 patients with early‐stage breast carcinoma by immunohistochemistry. HER‐2/neu gene amplification was investigated with automated fluorescent in situ hybridization. The mitotic activity index, histologic grade, and tumor type were assessed in hematoxylin and eosinstained specimens. Clinical data included disease‐free survival, overall survival, lymph node status, and tumor size. The data were analyzed with two‐sided univariate and multivariate tests, with P values < 0.05 considered significant.RESULTSHigh levels of HIF‐1α had an association of borderline significance with decreased overall survival (P = 0.059) and disease‐free survival (P = 0.110) that was ascribed completely to the subgroup of women with lymph node negative tumors (n = 81 patients; P = 0.008 and P = 0.004, respectively). HER‐2/neu immunoreactivity (P < 0.001) and gene amplification (P < 0.001), vascular endothelial growth factor expression (P = 0.016), and Ki‐67 expression (P < 0.001) were correlated strongly with HIF‐1α positivity, although none of those factors had an independent effect on survival.CONCLUSIONSIncreased levels of HIF‐1α were associated independently with shortened survival in patients with lymph node negative breast carcinoma. Therefore, the use of immunohistochemical assessment of HIF‐1α as a new predictor of poor outcome may improve clinical decision‐making regarding adjuvant treatment of patients with lymph node negative breast carcinoma. Cancer 2003;97:1573–81. © 2003 American Cancer Society.DOI 10.1002/cncr.11246