Coexistence of HER2 over-expression and p53 protein accumulation is a strong prognostic molecular marker in breast cancer

INTRODUCTION: Many laboratories are currently evaluating the usefulness of determination of HER2, p53, and Ki67 proliferation indices using immunohistochemical techniques in cancer. Although the available studies suggest that these factors might indeed be helpful in making treatment decisions in cancer patients, their clinical usefulness is still controversial. METHODS: Expression of HER2, p53, and Ki67 was examined by immunohistochemistry in samples of breast tissue from 506 patients with invasive ductal carcinoma, obtained between 1981 and 1999 (median follow up period 82 months), and their significance for prognosis was analyzed. RESULTS: Of the 506 carcinoma tissue samples, 20.1%, 29.0%, and 53.6% were positive for HER2 over-expression, p53 protein accumulation, and Ki67 expression, respectively. Over-expression of HER2 significantly reduced disease free (P = 0.02) and overall survival (P = 0.005). Accumulation of p53 protein significantly decreased disease free (P = 0.01) and overall survival (P = 0.01). Patients with tumors that were positive for both HER2 and p53 relapsed and died within a significantly shorter period of time after surgery (P = 0.0001 and P < 0.0001, respectively). In multivariate analysis, patients with both HER2 and p53 positive tumors had considerably decreased overall survival (P = 0.04), as did patients with larger tumor size and positive lymph node status. CONCLUSION: The findings of the present study indicate that the coexistence of HER2 over-expression and p53 protein accumulation is a strong prognostic molecular marker in breast cancer

Quantitative determination, by real-time reverse transcription polymerase chain reaction, of aromatase mRNA in invasive ductal carcinoma of the breast

BACKGROUND: Estrogen is a mitogenic factor that is implicated in the genesis and progression of breast cancer via its binding to estrogen receptor (ER)-α. Synthesis of estrogen in situ is believed to be catalyzed mainly by aromatase. Previous studies comparing the relative contributions from tumor cells and stromal cells to local estrogen synthesis, as assessed by immunohistochemical analysis, were quite controversial and no consistent relationship was found between the presence of aromatase and any clinicopathologic factor. In addition, previous studies into aromatase gene expression and clinicopathologic factors are limited. METHODS: We assessed the level of expression of aromatase mRNA, using quantitative real-time RT-PCR, in 162 cases of invasive ductal carcinoma of the breast. Associations between aromatase expression and different clinicopathologic factors were sought. RESULTS: It was found that aromatase mRNA was expressed at significantly higher levels in patients older than 50 years, in those without axillary lymph node involvement, in those with tumor size less than 2 cm, and in ER-α positive tumors. However, no relationship was found between aromatase mRNA expression and any other clinicopathologic factor, including histologic grade and progesterone receptor status. Patients with high levels of expression of aromatase mRNA tended to have a better prognosis than did those patients with low expression. CONCLUSION: These findings imply that ER-α and aromatase may be coexpressed in endocrine responsive patients. They may also indicate that aromatase expression could be a marker of endocrine responsiveness, and it may have prognostic implications for breast cancer progression

Phosphorylation of estrogen receptor α serine 167 is predictive of response to endocrine therapy and increases postrelapse survival in metastatic breast cancer

INTRODUCTION: Endocrine therapy is the most important treatment option for women with hormone-receptor-positive breast cancer. The potential mechanisms for endocrine resistance involve estrogen receptor (ER)-coregulatory proteins and crosstalk between ER and other growth factor signaling networks. However, the factors and pathways responsible for endocrine resistance are still poorly identified. METHODS: Using immunohistochemical techniques, we focused on the expression and phosphorylation of hormone receptors themselves and examined the phosphorylation of ER-α Ser118 and ER-α Ser167 and the expression of ER-α, ER-β1, ER-βcx/β2, progesterone receptor (PR), PRA, and PRB in the primary breast carcinomas of 75 patients with metastatic breast cancer who received first-line treatment with endocrine therapy after relapse. RESULTS: Phosphorylation of ER-α Ser118, but not Ser167, was positively associated with overexpression of HER2, and HER2-positive tumors showed resistance to endocrine therapy. The present study has shown for the first time that phosphorylation of ER-α Ser167, but not Ser118, and expression of PRA and PRB, as well as ER-α and PR in primary breast tumors are predictive of response to endocrine therapy, whereas expression of ER-β1 and ER-βcx/β2 did not affect response to the therapy. In addition, patients with either high phosphorylation of ER-α Ser167, or high expression of ER-α, PR, PRA, or PRB had a significantly longer survival after relapse. CONCLUSION: These data suggest that phosphorylation of ER-α Ser167 is helpful in selecting patients who may benefit from endocrine therapy and is a prognostic marker in metastatic breast cancer

Estrogen binding capacity in cytosol fraction of human uterine cervix : effect of estrogen and anti-estrogens

The estrogen binding activity in the human uterine cervix was measured, and the effect of natural and synthesized steroids on the activities was determined. To assay the estrogen binding activity, the asmple was incubated with 10nM [(3)H] estradiol-17β at 30℃ for 2 hours. Then dextran-coated charcoal (DCC) was added to a final concentration of 0.5% to separate bound/free (B/F) estradiol. Estrogen binding activity was determined by subtracting the activity found in the heated sample from the corresponding activity in the untreated sample. For this purpose it was found appropriate to heat the sample at 40℃ for 60 minutes. The dissociation constant obtained from the Scatchard plot analysis was : kd=2.0×10(-9)M. A variety of steroids at the same molar concentration (1.0 μM) were added to the sample to determine their effects on the estrogen binding activity. For binding with [(3)H] estradiol-17β, the synthetic estrogens were strongly inhibitory, the anti-estrogen agents were strong-ly to moderately inhibitory. Dannazol, which has been used for the treatment of en-dometriosis, was found to be as effective as androgens. All of those inhibitory effects occur-red in a non-competitive manner

Estrogen binding capacity in cytosol fraction of human uterine cervix : effect of estrogen and anti-estrogens

The estrogen binding activity in the human uterine cervix was measured, and the effect of natural and synthesized steroids on the activities was determined. To assay the estrogen binding activity, the asmple was incubated with 10nM [(3)H] estradiol-17β at 30℃ for 2 hours. Then dextran-coated charcoal (DCC) was added to a final concentration of 0.5% to separate bound/free (B/F) estradiol. Estrogen binding activity was determined by subtracting the activity found in the heated sample from the corresponding activity in the untreated sample. For this purpose it was found appropriate to heat the sample at 40℃ for 60 minutes. The dissociation constant obtained from the Scatchard plot analysis was : kd=2.0×10(-9)M. A variety of steroids at the same molar concentration (1.0 μM) were added to the sample to determine their effects on the estrogen binding activity. For binding with [(3)H] estradiol-17β, the synthetic estrogens were strongly inhibitory, the anti-estrogen agents were strong-ly to moderately inhibitory. Dannazol, which has been used for the treatment of en-dometriosis, was found to be as effective as androgens. All of those inhibitory effects occur-red in a non-competitive manner