Relaxins are known for their tissue remodeling capacity which is also a hallmark of cancer progression. However, their role in the latter context is still unclear, particularly in breast cancer. In a mouse model with spontaneously arising breast cancer due to erbB2-overexpression we show that exposure to porcine relaxin results in significantly enhanced tumour growth as compared to control animals. This is accompanied by increased serum concentrations of progesterone and estradiol as well as elevated expression of the respective receptors and the relaxin receptor RXFP1 in the tumour tissue. It is also associated with enhanced infiltration by tumour-associated macrophages which are known to promote tumour progression. Additionally, we show in an ex vivo model of metastatic brain colonization that porcine relaxin as well as human brain-specific relaxin-3 promotes invasion into the brain tissue and enhance interaction of breast cancer cells with the resident brain macrophages, the microglia. Relaxin signaling is mediated via RXFP1, since R 3/I5, a specific agonist of the relaxin-3 receptor RXFP3 in the brain, does not significantly enhance invasion. Taken together, these findings strongly support a role of relaxins in the progression of breast cancer where they foster primary tumour growth as well as metastatic colonization by direct and indirect means.Electronic supplementary materialThe online version of this article (doi:10.1007/s10585-013-9609-2) contains supplementary material, which is available to authorized users.

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Background: Bone marrow-derived endothelial progenitor cells (EPCs) constitute an important part of the tumor microenvironment and are critical for metastatic progression in preclinical models and breast cancer patients (Jain et al, Breast Cancer Res Treat, 2012). Tetrathiomolybdate (TM), a copper-depleting compound inhibits angiogenesis, tumor growth, and metastasis. This study explores the effect of TM on EPCs in patients at high risk for breast cancer recurrence. Methods: This phase II study enrolled stage 3, 4 without evidence of disease (NED), and any node-positive triple negative breast cancer patient. Only concomitant hormone therapy was allowed. Patients received induction TM 180 mg daily at baseline followed by an equal or lower daily dose (median 100 mg, range 0–140) to maintain ceruloplasmin (Cp) level < 17 mg/dl (target for copper depletion). We monitored EPCs (CD45dim/CD133+/VEGFR2+), Cp, CEA, and CA15-3 at baseline and monthly. Wilcoxon signed-rank was used to compare Cp and EPC levels between baseline and subsequent time points. All p-values were two-sided with statistical significance evaluated at the 0.05 alpha level. Results: 50 patients (33 adjuvant, 17 Stage 4 NED, and 22 triple negative) were enrolled. In the first 40 patients enrolled who had received at least 24 months of TM, EPC and Cp data were available for analysis. Of these 40 patients, 1 patient did not take TM due to patient preference, and 736 cycles of TM (average 18.9 per patient) were administered. Median age was 50 years (range 29–66). Median number of tumor size and positive lymph nodes among adjuvant patients were 3.5 cm (range 1.2–7) and 9 (range 0–42), respectively. Of the patients receiving hormone therapy, 11 patients were on tamoxifen and 16 patients were on an aromatase inhibitor. Median baseline Cp level was 30 mg/dL (range 20–47). 71% patients adequately copper depleted at month 1 to a mean Cp of 14.8 mg/dL. A larger proportion of triple negative patients copper depleted (82%) compared to hormone receptor positive subtypes (47%) and HER2/neu positive subtypes (67%). Median EPCs/ml decreased from baseline to last dose by 16 in patients that achieved the copper depletion target, p = 0.014. Conversely, in patients that did not copper deplete, median EPCs/ml increased by 136, p = 0.005. Of the 50 patients on study, 7 patients relapsed in which a significant increase in EPCs preceded an objective clinical relapse and a tumor marker rise by a median of 1 month. Only grade 3/4 toxicity was hematologic, occurred in 49 cycles (6.7%), and resolved in 5–13 days with TM held and resumed at a lower dose. Conclusions: TM is a well-tolerated oral copper chelator that may contribute to maintaining EPCs below baseline in copper-depleted patients. Molecular subtype may impact on the ability to copper deplete. EPCs may have potential as a surrogate marker for early relapse and as a therapeutic target for interrupting the metastatic progression. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-11-04.

Background: Peripheral neuropathy is a dose-limiting toxicity of most microtubule-stabilizing chemotherapeutic agents. Ixabepilone, a semisynthetic analog of the natural epothilone B, has activity in a wide range of tumors including taxane-resistant disease. In this study, we sought to understand the effect of ixabepilone on the development of peripheral neuropathy both clinically and its effect at the ultrastructural level of the peripheral nerves and circulating factors over time. Parallel studies in animal models of neuropathy were performed at the same time (Proc AACR 2010 Abstract 4184). Methods: This open-label, non-randomized phase II study enrolled 14 patients with metastatic breast cancer. Ixabepilone was administered by 2 schedules: the FDA approved dose of 40 mg/m2 every 3 weeks (q3w) and 16 mg/m2 on day 1, 8, and 15 of a 28-day cycle (weekly). Five controls, 2 with residual taxane-associated peripheral neuropathy and 3 with no prior chemotherapy or peripheral neuropathy, were also accrued. The primary objectives were to characterize the natural history of ixabepilone-associated peripheral neuropathy using the Total Neuropathy Score Clinical (TNSc) assessment tool prior to each cycle and to correlate changes in the ultrastructure of dermal myelinated nerve fibers via a 3 mm punch biopsy of an area 10 cm above the lateral malleolus every 2 cycles with electron microscopy (EM), as well as circulating factors (both inflammatory and neurotrophic) considered to be important in the pathogenesis of chemotherapy-induced peripheral neuropathy. Secondary objectives included progression-free survival (PFS) and non-neurologic toxicity. Results: 14 patients were enrolled and were equally divided between the 2 schedules of ixabepilone chemotherapy. There were no differences in baseline characteristics between the two groups. Mean age was 54 years (range 32–71). Mean number of previous chemotherapy regimens was 3.5 (range 0–8). 57% of patients had received a taxane in the adjuvant setting and 64% in the metastatic setting. The mean neuropathy score (TNSc) at baseline was 4.6 (range 1–11). At a mean cumulative dose of 185 mg/m2, the TNSc with ixabepilone q3w schedule was 3.7 points higher/worse (95% CI: 2.2–5.3, p = 0.03) than the mean score observed in patients on the weekly schedule. The sensory component was most significantly affected, predominantly numbness. In 3 patients, the chemotherapy schedule was changed from every 3 weeks to weekly due to > grade 2 toxicity at a mean cumulative dose of 107 mg/m2, and TNSc decreased/improved by 2.7 points. PFS in patients on q3w ixabepilone was 133 days (range 28–280) and in patients on weekly ixabepilone was 179 days (range 66–336), nonsignificant. Evaluation of EM and circulating factors is ongoing. Conclusions: Weekly ixabepilone appears to have a more favorable neurotoxicity profile compared to the standard q3w schedule. Integration of the EM data and the circulating factor data are underway and will be presented. Ixabepilone-associated peripheral neuropathy may improve in patients switched to weekly ixabepilone without compromising efficacy. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-15-07.