Introduction:The PTEN gene, a candidate tumor suppressor, is localized to chromosome 10q23 and shares extensive homology with cytoskeletal proteins auxilin and tensin. A high frequency of mutations at the PTEN locus has been described in a variety of neoplasms including breast cancer. However, the role of PTEN alternations and its association with outcome variables in breast neoplasia is not well established. Design: Formalin-fixed paraffin embedded tissues from 151 women (mean age 62 years, range 26 -98) with primary diagnosis of invasive breast cancer were evaluated for PTEN protein expression by automated immunohistochemical methods. Slides were scored semi-quantitatively based on staining intensity and distribution, and results were compared with clinical pathologic parameters. The mean follow-up was 56 months (range 1-169). Results: Seventy-three (48%) of 151 breast tumors had loss of PTEN protein expression. On univariate analysis, loss of PTEN expression (P ‫؍‬ .034), stage (P < .0001), node positive (P < .0001), and tumor grade (P ‫؍‬ .002) were associated with disease-related death. Loss of PTEN expression also predicted lymph node metastasis (P < .0001), and correlated with loss of estrogen receptor staining (P ‫؍‬ .040). Loss of PTEN did not correlate with stage, tumor grade, disease recurrence, or loss of progesterone receptor [although a trend was seen (P ‫؍‬ .092). On multivariate analysis, stage (P < .0001), lymph node metastasis (P < .0001), and tumor grade (P ‫؍‬ .002) correlated with survival. Conclusion: Loss of PTEN protein expression occurs commonly in breast cancer and correlates with disease related death, lymph node metastasis, and loss of estrogen receptor staining. Our results support the

Topoisomerase II␣ (topo II␣) plays a key role in DNA replication and is a target for multiple chemotherapeutic agents. In breast cancer, topo II expression has been linked to cell proliferation and HER2/ neu protein overexpression. However, its relationship with outcome variables is not well established.Formalin-fixed, paraffin-embedded primary breast cancers from 184 women (mean age, 60 years) were stained for topo II by automated immunohistochemistry. A topo II expression index ( Topoisomerase II␣ (topo II␣) is a component of the DNA machinery that is intricately involved at many levels of DNA metabolism (1-3). Its primary function is to alter DNA topology from its storage (supercoiled) form to a more exposed (partially uncoiled) form by inducing single-strand DNA breaks and simultaneously passing another intact double helix through the gap (4 -5). The anthracycline class of antitumor cytotoxic drugs is topoisomerase poisons specifically targeting topo II␣ (2, 6 -7). These drugs create a cleavable complex including drug, topo II␣, and DNA strand. It is hypothesized that the cleavable complex damages the DNA, causing toxicity, and may induce apoptosis in proliferating tumor cells (8 -10). From most in vitro analyses, it has been shown that low levels of topo II␣ expression in cancer cells are associated with drug resistance, whereas high levels indicate sensitivity (11-13). However, in one study, no correlation between the level of topo II␣ expression and drug sensitivity in breast cancer cell lines was found (14), and recent reports using paraffinembedded breast cancer tissues failed to find associations between topo II␣ expression and drug sensitivity (15).

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The HER-2/neu oncogene, localized to chromosome 17q, shares substantial homology with the epidermal growth factor receptor. HER-2/neu gene amplification and protein overexpression have been associated with poor prognosis in breast cancer. Formalin-fixed paraffin-embedded primary invasive breast cancer tissues from 135 women were tested for HER-2/neu gene amplification by automated fluorescence in situ hybridization (FISH) using a sequence probe. The tumors also were evaluated by immunohistochemistry for proliferation markers Ki 67 (MIB1) and p34cdc2 cyclin-dependent kinase. Patients were followed up for a mean of 61 months. There were 70 node-negative and 65 node-positive cases. Ki 67 and p34cdc2 proliferation marker overexpression, HER-2/neu oncogene amplification, large tumor size, high tumor grade, advanced tumor stage, positive lymph node status, and distant metastasis at the time of diagnosis predicted disease-related death in combined node-negative and node-positive breast cancer. HER-2/neu gene amplification, tumor stage, lymph node metastasis, tumor grade, and distant metastasis at the time of diagnosis independently predicted disease outcome. HER-2/neu amplification detected by FISH also predicted disease-related death independent of lymph node status, tumor grade, and distant metastasis in breast cancer patients who received adjuvant therapy.