Recent advances in breast cancer (the Twenty-fourth San Antonio Breast Cancer Symposium, December, 2001).

This paper reviews the Twenty-fourth Annual San Antonio Breast Cancer Symposium. The preliminary results of the ATAC study have shown that Arimidex is superior to tamoxifen in postmenopausal women with ER-positive early breast cancer in terms of DFS, adverse effects and prevention of contralateral breast cancer. However, longer follow up is required to assess the drug safety regarding bone mineral density and cognitive function. Letrozole seems to be superior to tamoxifen as a first-line therapy in ER-positive advanced breast cancer in postmenopausal women. Although the incidence of acute myeloid leukaemia is significantly increased (cumulative incidence at 5 years = 1.1%) in breast cancer patients receiving cyclophosphamide and anthracyclines, the risk of this complication is easily outweighed by the benefits of chemotherapy. Adjuvant clodronate was found to be associated with a significant reduction in the incidence of bone metastases during the treatment period. A randomised trial comparing axillary dissection and axillary radiotherapy (RT) for early breast cancer reported no significant difference in survival at 15 years. However, axillary recurrence was significantly increased in the RT group. hTERT protein expression by IHC was found to correlate significantly with breast cancer-specific survival. There is no evidence to support the use of IHC of the sentinel node in routine clinical practice. LCIS is currently considered as a non-obligate precursor to breast cancer rather than just a risk factor.

Cyclo-oxygenase-2 (COX-2) mRNA expression correlates with progesterone receptor positivity in human breast cancer.

BACKGROUND: We previously presented evidence showing that cyclo-oxygenase 2 (COX-2) plays an important role in mammary carcinogenesis and angiogenesis in human breast cancer. The present study aims to compare COX-2 mRNA expression with hormone receptor status, S-phase fraction, telomerase activity, and DNA ploidy in human breast cancer. METHODS: Total cellular RNA was extracted from frozen breast tissue samples according to standard methodology. The mRNA copy numbers for COX-2 were determined in 18 infiltrating carcinomas using quantitative RT-PCR and TaqMan methodology. The oestrogen receptor (ER) and progesterone receptor (PgR) status was determined using the ligand-binding technique (ER+ = > 3 fmol/mg, PgR+ = > 5 fmol/mg). We also determined DNA ploidy status (diploid or aneuploid), S-phase fraction (< 6% = low, 6-10% = intermediate, > 10% = high), and telomerase activity (total protein generated by TRAP assay). RESULTS: The median COX-2 mRNA copy number per micro g of RNA was 126 713 (range = 15 717-2 022 050). COX-2 expression was significantly associated with PgR positivity (p = 0.013). The association between COX-2 and DNA diploidy failed to reach a statistical significance (p = 0.085). No significant association was detected between COX-2 and S-phase fraction, ER status, or telomerase activity. CONCLUSIONS: COX-2 mRNA expression is associated with PgR positivity in human breast cancer. This observation is consistent with the hypothesis that COX-2 upregulates aromatase activity.

The significance of human telomerase reverse transcriptase (hTERT) in cancer.

Since the discovery of the enzyme telomerase in humans, it has become apparent that it is the most general of tumour markers known, and enormously significant in its potential for diagnostic, prognostic and therapeutic applications. Extensive work has identified three core components of the enzyme, of which the catalytic subunit hTERT (human telomerase reverse transcriptase) appears to be the most important. The aim of this article is to review the current evidence for the function and activity of hTERT in malignant conditions, and to discuss the future possibilities in terms of cancer diagnosis and treatment.

hTERT mRNA expression correlates with telomerase activity in human breast cancer.

AIMS: Telomerase is a ribonucleoprotein enzyme that synthesises telomeres after cell division and maintains chromosomal length and stability thus leading to cellular immortalisation. hTERT (human telomerase reverse transcriptase) gene seems to be the rate-limiting determinant of telomerase reactivation. hTERT mRNA expression was reported to correlate with telomerase activity in cell lines and some human tumours. However the correlation between telomerase activity and hTERT mRNA expression has not been previously examined in human breast cancer. The present study aims to quantitatively measure the expression of hTERT mRNA and telomerase activity in human breast cancer and examine the relationship between these parameters. Furthermore the associations with other parameters including estrogen receptor (ER) and progesterone receptor (PgR) status, DNA ploidy, and S-phase fraction (SPF) are also examined. METHODS: RNA was extracted from 18 breast carcinomas and hTERT mRNA expressions were estimated by reverse transcriptase-PCR (RT-PCR) and Taqman methodology. These tumours had already been analysed for ER and PgR status using ligand-binding assays and had had their DNA ploidy and S-phase fractions measured by flow cytometry. Telomerase activity had already been determined by using a modified telomeric repeat and amplification protocol (TRAP) assay. RESULTS: The expression of hTERT mRNA in the breast tumours ranged between 1.3 and 2.7 x 10(7) copy numbers per micro g of cellular RNA (the median value was 2.7x10(5) and the mean was 3.1 x 10(6)). Telomerase activity was between 0 and 246 units of Total Protein Generated (TPG), where one unit of TPG was equal to 600 molecules, of telomerase substrate primers extended by at least three telomeric repeats. The median level of TPG was 60 units and the mean level was 81 units). Telomerase activity was found to significantly correlate with hTERT expression (r(s)=0.51112, P=0.0302). There was no significant correlation between hTERT and other parameters. CONCLUSION: hTERT mRNA expression significantly correlates with telomerase activity in human breast cancer. This is consistent with the hypothesis that hTERT is the catalytic and rate-limiting determinant subunit of the enzyme.

hTERT expression in human breast cancer and non-cancerous breast tissue: correlation with tumour stage and c-Myc expression.

Telomerase is a ribonucleoprotein enzyme that synthesises telomeres after cell division and maintains chromosomal length and stability thus leading to cellular immortalisation. hTERT (human telomerase reverse transcriptase) gene is the rate-limiting determinant of telomerase reactivation. The present study aims to quantitatively measure the expression of hTERT mRNA in human breast cancer, adjacent non-cancerous tissue (ANCT) and benign breast lesions, examine the association between hTERT and the clinicopathological characteristics of the cancer specimens and to explore the relationship between c-Myc and hTERT expressions. RNA was extracted from 49 breast carcinomas, 46 matched ANCT, and eight fibroadenomas. hTERT and c-Myc mRNA expressions were estimated by reverse transcriptase-PCR (RT-PCR) and Taqman methodology. hTERT mRNA was present in all of the cancerous and most of ANCT specimens with levels being much higher in the cancerous tissue than in ANCT. The ratio of hTERT mRNA in tumour to that in ANCT was 2011 (95% confidence interval 373-10,853, P < 0.0001). There was no significant association between tumour hTERT expression and patient's age, tumour size, grade, nodal metastasis, estrogen receptor (ER) positivity, lymphovascular (LVI) or c-Myc expression. However, there was a weak but significant negative correlation between hTERT expression and progesterone receptor (PR) status (p = 0.04) in tumours. hTERT mRNA expression was also significantly higher in carcinomas (median = 2.61 x 10(6)) than in fibroadenomas (median = 424).We conclude that hTERT mRNA expression is significantly higher in human breast cancer than in non-cancerous breast tissue suggesting that hTERT has a potential role in breast cancer diagnosis. The hTERT mRNA levels in tumour do not seem to be associated with the patient's age or advanced tumour stage. Furthermore, hTERT mRNA expression does not correlate with c-Myc mRNA expression in breast cancer.