Chemokines are implicated in tumor pathogenesis, although it is unclear whether they affect human cancer progression positively or negatively. We found that activation of the chemokine receptor CCR5 regulates p53 transcriptional activity in breast cancer cells through pertussis toxin–, JAK2-, and p38 mitogen–activated protein kinase–dependent mechanisms. CCR5 blockade significantly enhanced proliferation of xenografts from tumor cells bearing wild-type p53, but did not affect proliferation of tumor xenografts bearing a p53 mutation. In parallel, data obtained in a primary breast cancer clinical series showed that disease-free survival was shorter in individuals bearing the CCR5Δ32 allele than in CCR5 wild-type patients, but only for those whose tumors expressed wild-type p53. These findings suggest that CCR5 activity influences human breast cancer progression in a p53-dependent manner.

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Paclitaxel plus gemcitabine given as an every 2-weeks schedule is a well tolerated and active regimen in advanced breast carcinoma. This is an attractive combination to use when anthracyclines are not indicated, such as in HER2 positive cases that receive trastuzumab. In addition, elevated levels of HER2 ECD adversely affect the efficacy of treatment.

Summary It has been suggested that angiogenesis and angiogenic factors may be strong predictors of relapse in patients with breast carcinoma. We measured the levels of the angiogenic peptide basic fibroblast growth factor (bFGF) in 140 breast tumour cytosols using an immunoassay. There were no significant differences in bFGF levels between breast non-malignant lesions and primary carcinomas. In 124 cases with primary breast cancer, we observed an association of low bFGF levels (< 400 pg mg-') with increasing tumour size (P = 0.023) and stage of disease (P= 0.002). bFGF levels did not correlate with other variables, including axillary nodes, hormone receptors, cathepsin D and the serum tumour markers CA15.3 and CEA. With a median follow-up of 44.0 months, breast cancer patients with low levels of bFGF had a significantly shorter disease-free survival (DFS) than patients with elevated bFGF (log-rank, P < 0.0001). In a multivariate analysis of DFS, only bFGF, T-stage and histological grade showed statistical significance. In a parallel evaluation of circulating bFGF, we did not observe a correlation between the serum and tissue bFGF levels in the 29 selected cases with matched determinations. Our results indicate that low bFGF levels in breast carcinoma are an independent prognostic indicator of poor prognosis and disease recurrence.

It has been suggested that exogenous unsaturated fatty acids (UFAs) may increase the cytotoxic activity of cancer chemotherapeutic agents. We examined how y-linolenic acid (GLA; 18: 3n-6), the most promising UFA in the treatment of human tumors, affects the effectiveness of the lipophilic drug vinorelbine (VNR) on human breast carcinoma cell lines. Cells were exposed simultaneously to VNR and GLA or sequentially to GLA followed by VNR. Cell viability was determined by MTT assay. The increase in VNR-induced cell growth inhibition was measured by dividing the IC50 and IC70 values (50 and 70% inhibitory concentrations, respectively) that were obtained when the cells were exposed to VNR alone with those with VNR plus GLA. We found that GLA enhanced in a dose-dependent manner the cell growth inhibitory activity of VNR on MCF-7 cells (up to 9-fold). As GLA by itself showed anti-proliferative effects, possible GLA-VNR interactions at the cellular level were assessed employing the isobologram analysis and the combination index (CI) method of Chou-Talalay. Both methods showed an overall synergism between GLA and VNR in MCF-7 cells. At a high level of cell kill, the synergism was greater when a 24 h GLA pre-exposure or co-exposures were tested. Synergy was likewise observed with the GLA-VNR combination in MDA-MB-231, T47D, and SK-Br3 breast cancer cells. In all cell lines, the synergism was independent of the treatment schedule and the exposure time. Under conditions inhibiting lipid peroxidation using Vitamin E (dl-alpha-tocopherol), the enhancing effect of GLA (an easily oxidizable UFA) on VNR activity was partially abolished. However, when Vitamin E was used in combination, a similar synergistic increase in growth inhibition was obtained. These latter observations strongly implies that the synergistic effects of GLA with VNR are not mediated through a mechanism involving a generation of lipoperoxides. For comparison, the effects of other UFAs were examined on VNR chemosensitivity: GLA was the most potent at enhancing VNR activity, followed by docosahexaenoic acid (22: 6n-3), eicosapentaenoic acid (20: 5n-3) and alpha-linolenic acid (18: 3n-3), whereas linoleic acid (18: 2n-6) and arachidonic acid (20: 4n-6) did not increase VNR chemosensitivity. Very high concentrations of oleic acid (OA; 18:1 n-9), an UFA inversely correlated with breast cancer risk, also enhanced VNR effectiveness. Thus, various types of UFAs were not equivalent with respect to their actions on VNR effectiveness. In conclusion, our results give experimental support to the hypothesis that some UFAs can be used as modulators of tumor cell chemosensitivity and provide the rationale for in vivo preclinical investigation.