Transcriptional expression of 8 genes predicts pathological response to first-line docetaxel + trastuzumab-based neoadjuvant chemotherapy.

Background: Overexpression of HER2 is observed in 20 to 30% of breast carcinomas. The use of trastuzumab has improved the treatment of these patients, especially when it is associated with docetaxel. To optimize the use of this treatment, it seems important to select putative complete responders before treatment administration.

Transcriptional regulation of the survivin gene.

Survivin, a small member of the inhibitors of the apoptosis protein family, is highly deregulated in cancer. It is weakly expressed in normal tissues but very strongly expressed in malignant lesions. Survivin is involved in cell-cycle progression, especially in the G2/M transition, and has anti-apoptotic activity, which correlates with its strong expression in cases with a poor cancer treatment response and poor outcomes.

Survivin-3B potentiates immune escape in cancer but also inhibits the toxicity of cancer chemotherapy.

Dysregulation in patterns of alternative RNA splicing in cancer cells is emerging as a significant factor in cancer pathophysiology. In this study, we investigated the little known alternative splice isoform survivin-3B (S-3B) that is overexpressed in a tumor-specific manner. Ectopic overexpression of S-3B drove tumorigenesis by facilitating immune escape in a manner associated with resistance to immune cell toxicity.

Only missense mutations affecting the DNA binding domain of p53 influence outcomes in patients with breast carcinoma.

The presence of a TP53 gene mutation can influence tumour response to some treatments, especially in breast cancer. In this study, we analysed p53 mRNA expression, LOH at 17p13 and TP53 mutations from exons 2 to 11 in 206 patients with breast carcinoma and correlated the results with disease-free and overall survival. The observed mutations were classified according to their type and location in the three protein domains (transactivation domain, DNA binding domain, oligomerization domain) and correlated with disease-free and overall survival.

A short caspase-3 isoform inhibits chemotherapy-induced apoptosis by blocking apoptosome assembly.

Alternative splicing of caspase-3 produces a short isoform caspase-3s that antagonizes caspase-3 apoptotic activity. However, the mechanism of apoptosis inhibition by caspase-3s remains unknown. Here we show that exogenous caspase-3 sensitizes MCF-7 and HBL100 breast cancers cells to chemotherapeutic treatments such as etoposide and methotrexate whereas co-transfection with caspase-3s strongly inhibits etoposide and methotrexate-induced apoptosis underlying thus the anti-apoptotic role of caspase-3s.

Regulation of monocarboxylate transporter MCT1 expression by p53 mediates inward and outward lactate fluxes in tumors.

The monocarboxylate transporter (MCT) family member MCT1 can transport lactate into and out of tumor cells. Whereas most oxidative cancer cells import lactate through MCT1 to fuel mitochondrial respiration, the role of MCT1 in glycolysis-derived lactate efflux remains less clear. In this study, we identified a direct link between p53 function and MCT1 expression.

Apoptosis gene signature of Survivin and its splice variant expression in breast carcinoma.

Survivin, an anti-apoptotic protein, was described as strongly expressed in human cancers including breast cancer. However, little is known about the association between Survivin variants (Survivin-2B, Survivin-ΔEx3, Survivin-3B, and Survivin-2α) and the other apoptotic-related genes. In this study, we analyzed the apoptosis gene signature of Survivin and its variant expression in breast cancer.

Variations in gene expression and response to neoadjuvant chemotherapy in breast carcinoma.

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.

Predictive value of survivin alternative transcript expression in locally advanced breast cancer patients treated with neoadjuvant chemotherapy.

Survivin, a member of the apoptosis inhibitor protein family, is expressed in numerous human tumours, and its expression is described as a negative prognostic marker. Four alternative splice variants (survivin-DeltaEx3, survivin-3B, survivin-2B and survivin-2alpha) have been described. To date, little is known about the prognostic or predictive role of all five survivin transcripts in breast cancer.

The expression of BIRC5 is correlated with loss of specific chromosomal regions in breast carcinomas.

Expression of BIRC5 (survivin), a member of the inhibitor of apoptosis protein (IAP) family, is elevated in fetal tissues and in various human cancers. Mechanisms up-regulating BIRC5 in cancer are poorly understood. Here, we show that overexpression of BIRC5 induces a high proliferation level in MCF-7 breast tumor cells.

Patterns of loss of heterozygosity in breast carcinoma during neoadjuvant chemotherapy.

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.

Overexpression of caspase-3s splice variant in locally advanced breast carcinoma is associated with poor response to neoadjuvant chemotherapy.

Purpose: CASP-3 gene gives rise, by alternative splicing to a caspase-3s variant, to the antagonist apoptotic property of caspase-3. Deregulation of splicing in tumor cells favoring the expression of antiapoptotic variants has been reported to contribute to both tumorigenesis and chemoresistance. Thus, we investigated the role of caspase-3 and its splice variant in breast cancer cells.

Distinct expression of Survivin splice variants in breast carcinomas.

Survivin, a member of the inhibitor apoptosis family, is expressed in several human tumours, and its expression is regulated by p53. Recently, three alternative splice variants (Survivin-2B, Survivin-deltaEx3 and Survivin-3B), differing in their antiapoptotic properties, were identified. To date, little is known about the expression of all Survivin splice variants in breast cancer, particularly the recently identified Survivin-3B variant.

Comparative analysis of molecular alterations in fibroadenomas associated or not with breast cancer.

Hypothesis: The cause of breast cancer is linked to many macroscopic events, including benign breast disease. In this study we asked whether molecular changes could discriminate fibroadenoma, which is one of the most common benign breast disease lesions associated or not with breast cancer.

Design: Retrospective cohort study.

Analysis of microsatellite instability in acquired drug-resistance human tumor cell lines.

Genomic instability characterized as microsatellite instability (MIN) is associated with loss of DNA mismatch repair (MMR) protein. Several studies have shown that loss of DNA MMR protein confers resistance to some interacting DNA chemotherapeutic drugs, but also that exposure of MMR-proficient cells to these drugs can result in loss of MMR protein accompanied by induction of MIN. Such associations were mainly reported for cisplatin, but scarce data are available for doxorubicin (a DNA interacting agent), and nothing is known about vinblastine (an antitubulin agent).

Human colon cancer cells surviving high doses of cisplatin or oxaliplatin in vitro are not defective in DNA mismatch repair proteins.

Purpose: Alterations in the DNA mismatch repair (MMR) proteins have been associated with an increased resistance of many cancer cell lines to cisplatin. The aim of this work was to investigate whether defects in DNA MMR proteins are involved in the survival of human colorectal cancer cells in the presence of high concentrations of cisplatin and oxaliplatin, a diaminocyclohexane (DACH) platinum compound whose adducts are not recognized by the MMR system.

Methods: Six unselected human colon cancer cell lines (HT29, HCT15, HCT116, Caco2, SW480 and SW620) were treated with a single 3-h exposure to cisplatin or oxaliplatin at suprapharmacological concentrations, ranging from 50 to 200 microg/ml.

Breast carcinoma metastasis within granulosa cell tumor of the ovary: morphologic, immunohistologic, and molecular analyses of the two different tumor cell populations.

Gynecologic metastasis of breast carcinoma is not an infrequent event, but metastases within another tumor is very rare. We report a case of unilateral ovarian tumor arising in a 63-year-old woman receiving tamoxifen therapy with a past history of breast carcinoma. The microscopic appearance was principally that of a granulosa cell tumor, but the presence of atypical cells closely admixed within the classical areas was reminiscent of metastasis from breast carcinoma.