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IntroductionIntrinsic or acquired chemoresistance is a major problem in oncology. Although highly responsive to chemotherapies such as paclitaxel, most triple negative breast cancer (TNBC) patients develop chemoresistance. Here we investigate the role of BRCA1-IRIS as a novel treatment target for TNBCs and their paclitaxel-resistant recurrences.MethodsWe analyzed the response of BRCA1-IRIS overexpressing normal mammary cells or established TNBC cells silenced from BRCA1-IRIS to paclitaxel in vitro and in vivo. We analyzed BRCA1-IRIS downstream signaling pathways in relation to paclitaxel treatment. We also analyzed a large cohort of breast tumor samples for BRCA1-IRIS, Forkhead box class O3a (FOXO3a) and survivin expression. Finally, we analyzed the effect of BRCA1-IRIS silencing or inactivation on TNBCs formation, maintenance and response to paclitaxel in an orthotopic model.ResultsWe show that low concentrations of paclitaxel triggers BRCA1-IRIS expression in vitro and in vivo, and that BRCA1-IRIS activates two autocrine signaling loops (epidermal growth factor (EGF)/EGF receptor 1 (EGFR)-EGF receptor 2 (ErbB2) and neurogulin 1 (NRG1)/ErbB2-EGF receptor 3 (ErbB3), which enhances protein kinase B (AKT) and thus survivin expression/activation through promoting FOXO3a degradation. This signaling pathway is intact in TNBCs endogenously overexpressing BRCA1-IRIS. These events trigger the intrinsic and acquired paclitaxel resistance phenotype known for BRCA1-IRIS-overexpressing TNBCs. Inactivating BRCA1-IRIS signaling using a novel inhibitory mimetic peptide inactivates these autocrine loops, AKT and survivin activity/expression, in part by restoring FOXO3a expression, and sensitizes TNBC cells to low paclitaxel concentrations in vitro and in vivo. Finally, we show BRCA1-IRIS and survivin overexpression is correlated with lack of FOXO3a expression in a large cohort of primary tumor samples, and that BRCA1-IRIS overexpression-induced signature is associated with decreased disease free survival in heavily treated estrogen receptor alpha-negative patients.ConclusionsIn addition to driving TNBC tumor formation, BRCA1-IRIS overexpression drives their intrinsic and acquired paclitaxel resistance, partly by activating autocrine signaling loops EGF/EGFR-ErbB2 and NRG1/ErbB2-ErbB3. These loops activate AKT, causing FOXO3a degradation and survivin overexpression. Taken together, this underscores the need for BRCA1-IRIS-specific therapy and strongly suggests that BRCA1-IRIS and/or signaling loops activated by it could be rational therapeutic targets for advanced TNBCs.

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Background-Phase I studies in cancer have changed in recent years. With the advent of new less toxic targeted agents, more patients may now be candidates for new drug studies earlier in the course of their disease. It is to the advantage of the members of the oncology community to know more about the details and requirements for participation in early phase clinical trials so they can advocate for their patients and help them decide when such trials may be an appropriate choice. In order to examine the work intensity of early phase cancer clinical trials, we compared the study requirements of phase I and II protocols. Methods-As a surrogate of study complexity, we examined five parameters-number of physical exams, vital sign determinations, electrocardiograms (ECGs), non-pharmacokinetic laboratory tests, and pharmacokinetic (PK) sampling-in the first four weeks of protocol, in 90 studies (49 phase I and 41 phase II). Findings-From July 2004 through March 2007, there were 49 phase I trials in the Phase I Program, nine phase II studies conducted by physicians appointed in that program, and 32 phase II trials with accessible data in the Department of Thoracic/Head & Neck Medical Oncology. In the phase I versus phase II trials, there were significantly more (p < 0.05) physical exams (mean ± SE = 3.16 ± 0.24 vs. 2.22 ± 0.13), vital signs (5.63 ± 0.61 vs. 2.80 ± 0.26), ECGs (4.36 ± 1.16 vs. 0.80 ± 0.17), non-PK lab tests (18.08 ± 1.31 vs. 10.12 ± 0.65), and PKs (15.14 ± 1.79 vs 1.02 ± 0.53). These values were also significantly different (p<0.005 for each) when comparing medians by non-parametric tests. Interpretation-While both phase I and phase II trials have substantial study requirements, those for the phase I studies were significantly higher. Successful conduct of early phase clinical trials requires significant research infrastructure.