In this study, we performed a screening of 266 gene expressions in breast carcinomas and carried out correlations with histological response to either FEC-100 (fluorouracil-epirubicin-cyclophosphamide; n = 16) or Tax-Epi (docetaxel-epirubicin; n = 12) treatment. Gene expression in biopsies obtained before and after one course of chemotherapy was analyzed. Expression of specific genes was significantly changed after one course of chemotherapy, particularly for Tax-Epi treatment. Comparison with histological response for both treatments revealed that only good responders exhibited changes in gene-expression profile. These results agree that expression of different genes changes in response to anthracycline-based neoadjuvant chemotherapy and show, for the first time, that response to docetaxel-based treatment implied also changes in gene-expression profile.
Abstract. There is evidence indicating that resistance to some chemotherapy drugs is related to enhanced repair of DNA lesions. Microsatellite instability (MSI) and loss of heterozy-gosity (LOH) reflect genetic instability and are associated with specific DNA repair pathways. Despite the strong implication of genetic instability in breast cancer its association with chemotherapy is unknown. Thus, we analyzed microsatellite alterations with 12 markers in locally advanced breast carcinomas in relation to neoadjuvant epirubicin-cyclophosphamide-containing chemotherapy (FEC-100) and compared it to a docetaxol-based (Tax-Epi) regimen. Samples were obtained before, during and after treatments. In pre-treated samples, MSI was detected only in 2 cases (7%) whereas LOH was found in 23 of the 34 (68%) carcinomas including 10 belonging to the FEC-100 group and 13 to Tax-Epi one. LOH frequency decreased from the first course of both regimens, but differences between the patterns of LOH during treatment were found. Persistent LOH was more frequent in FEC-100 group (71% vs. 41%) that was detected only in biopsies belonging to nonresponder patients. Persistent LOH were clustered at particular loci located at regions containing common fragile sites (FHIT and FRA6E). Analysis of baseline LOH with 6 markers located at 3p indicates discontinuous patterns reflecting double-strand break (DSB) lesions. These results agree with a drug-dependent link between genetic instability and chemoresistance and show that FEC-100 treatment is associated with DSB accumulation manifested as LOH in tumor cells resistant to chemotherapy in breast carcinoma.
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