Data on breast cancer are outlined in reports from the United States and Germany.

Study 1: Increased PTEN expression due to transcriptional activation of PPAR gamma by Lovastatin and Rosiglitazone may provide novel therapeutic options.

According to recent research published in the International Journal of Cancer, “Germline mutations in the tumor suppressor gene PTEN (protein phosphatase and tensin homolog located on chromosome ten) predispose to heritable breast cancer. The transcription factor PPAR gamma has also been implicated as a tumor suppressor pertinent to a range of neoplasias, including breast cancer. A putative PPAR gamma binding site in the PTEN promoter indicates that PPAR gamma may regulate PTEN expression.”

“We show here,” proposed R.E. Teresi and colleagues, Cleveland Clinic Foundation, “that the PPAR gamma agonist Rosiglitazone, along with Lovastatin, induce PTEN in a dose- and time-dependent manner.”

They found, “Lovastatin- or Rosiglitazone-induced PTEN expression was accompanied by a decrease in phosphorylated-AKT and phosphorylated-MAPK and an increase in G1 arrest. We demonstrate that the mechanism of Lovastatin- and Rosiglitazone-associated PTEN expression was a result of an increase in PTEN mRNA, suggesting that this increase was transcriptionally-mediated. Compound-66, an inactive form of Rosiglitazone, which is incapable of activating PPAR gamma, was unable to elicit the same response as Rosiglitazone, signifying that the Rosiglitazone response is PPAR gamma-mediated.”

“To support this,” continued investigators, “we show, using reporter assays including dominant-negative constructs of PPAR gamma, that both Lovastatin and Rosiglitazone specifically mediate PPAR gamma activation. Additionally, we demonstrated that cells lacking PTEN or PPAR gamma were unable to induce PTEN mediated cellular events in the presence of Lovastatin or Rosiglitazone. These data are the first to demonstrate that Lovastatin can signal through PPAR gamma and directly demonstrate that PPAR gamma can upregulate PTEN at the transcriptional level.”

The researchers concluded, “Since PTEN is constitutively active, our data indicates it may be worthwhile to examine Rosiglitazone and Lovastatin stimulation as mechanisms to increase PTEN expression for therapeutic and preventative strategies including cancer, diabetes mellitus and cardiovascular disease.”

Teresi and colleagues published their study in International Journal of Cancer (Increased PTEN expression due to transcriptional activation of PPAR gamma by Lovastatin and Rosiglitazone. Int J Cancer, 2006;118(10):2390-2398).

For additional information, contact C. Eng, Cleveland Clinic Foundation, Lerner Research Institute, Genom Med Institute, 9500 Euclid Avenue, Cleveland, OH 44195, USA.

Study 2: Estrogen and radiation-induced breast cancer was associated to allelic imbalance at the 11q23-q24 chromosome.

According to recent research published in the International Journal of Oncology, “Multiple genetic alterations are common in cancers including those of the breast. The mechanisms leading to these alterations such as point mutations, gene amplifications, deletions and replication error are often associated with frequent and consistent loss of heterozygosity (LOH) or microsatellite instability (MSI).”

“Several cytological and molecular studies have shown high frequency loss of genetic information on the long arm of chromosome 11 (i.e., 11q) in various primary breast cancers,” explicated D. Roy and colleagues, Brookhaven National Laboratory. “In the present study allelic alterations in a refined position on the long arm of chromosome 11 were studied to identify the spectrum of induced damage at different stages of malignant transformation of MCF-10F cell lines after exposure to high-LET radiation using alpha-particles and exposure to estradiol by using PCR-single strand conformation polymorphism (SSCP) and fluorescence in situ hybridization (FISH) analysis.

“Microsatellite markers were selected from chromosome 11 (11q23-q24 loci) and it was found that frequency of allelic imbalance occurs at different stages of tumor progression with a range of 15-45% depending on the marker studied.”

The researchers concluded, “These results strongly suggested the presence of several tumor suppressor genes in this critical region of chromosome 11 (11q23-q24). It also represents the first indication of allele loss at these loci in human breast epithelial cells induced by radiation and estrogen treatment suggesting a potential interventional target in breast carcinogenesis.”

Roy and colleagues published their study in International Journal of Oncology (Allelic imbalance at 11q23-q24 chromosome associated with estrogen and radiation-induced breast cancer progression. Int J Oncol, 2006;28(3):667-674).

For additional information, contact D. Roy, Brookhaven National Laboratory, Dept. Biology, 463, 50 Bell Avenue, Upton, NY 11973, USA.

Study 3: Amplifications of the epidermal growth factor receptor (EGFR) gene were associated with progression of phyllodes tumor of the breast.

According to a study from Germany, “Phyllodes tumors of the breast are rare biphasic tumors with the potential for invasion and metastatic spread. An important role of the EGFR in phyllodes tumors has been proposed. However, detailed pathogenetic mechanisms remained unclear.”

“We investigated 58 phyllodes tumors of the breast (40 benign, 10 borderline and 8 malignant) by means of EGFR fluorescence in situ hybridization (FISH) and gene dosage PCR for a regulatory sequence within intron 1 of EGFR. Immunohistochemical staining was performed for EGFR, p16, p21, p27, p53, c-myc, Cyclin A, Cyclin D1, Cyclin E, c-kit and Ki67.

Immunopositivity for EGFR was detected in 19% of phyllodes tumors (75% of all malignant tumors) in stromal tumor cells but not in the epithelial component,” explained C. Kersting and colleagues, University of Munster.

“Whole-gene amplifications were seen by FISH in 15.8% (in stromal cells only) and intron 1 amplifications by gene dosage PCR in as much as 41.8% of all phyllodes tumors.

Significant correlations were seen between tumor grade on the one hand and EGFR overexpression (p=.001) and intron 1 amplifications (p>.05) on the other. EGFR overexpression further correlated positively with immunohistochemical staining for p53, p16, Cyclin A, Cyclin E, Ki67 and c-kit. Presence of intron 1 amplifications correlated with p16 (p<.01), p21 (p=.009) and p53 immunoreactivity (p<.001). Neither EGFR overexpression nor whole-gene amplification was observed in a control series of 167 fibroadenomas and only 1 of 43 (2.3%) exhibited intron 1 amplification in gene dosage PCR.”

The researchers concluded, “Our results show for the first time that activating mutations in and overexpression of EGFR are associated with the progression in grade of phyllodes tumors of the breast. The observed association between intron 1 amplification and overexpression of EGFR provides further insight into regulation mechanisms of EGFR overexpression.”

Kersting and colleagues published their study in Laboratory Investigation (Amplifications of the epidermal growth factor receptor gene (EGFR) are common in phyllodes tumors of the breast and are associated with tumor progression. Lab Invest, 2006;86(1):54-61).

For more information, contact H. Buerger, University of Munster, Institute Pathology, Albert Schweitzer Str 33, D-48149 Munster, Germany.