Prospective evaluation of estrogen receptor-beta in predicting response to neoadjuvant antiestrogen therapy in elderly breast cancer patients.

It has been proposed that knowledge of estrogen receptor beta (ER-beta) expression may refine estrogen receptor alpha (ER-alpha) predictivity of response to endocrine therapy. We challenged this hypothesis in ER-alpha-positive breast cancers subjected to preoperative antiestrogen treatment. Forty-seven elderly (> or =65 years old) women with nonmetastatic, ER-alpha-positive (by immunohistochemistry) primary breast cancers (> 2 cm in diameter) entered a neoadjuvant hormone therapy protocol (60 mg/day toremifene for 3 months). ER-alpha and ER-beta (ERs) mRNA was determined by semiquantitative RT-PCR, before (on core needle biopsy) and after (on surgical specimens) neoadjuvant treatment. Study end points included: (1) relation between treatment response and ER mRNA expression; and (2) changes in ER expression after treatment. The response was clinically assessed as tumor size change at the end of the preoperative treatment. ER mRNA expression was assessable before and after treatment in 38 and 20 cases respectively. ER-beta was co-expressed with ER-alpha at variable levels and significantly correlated only with progesterone receptor (P = 0.0285). Objective clinical response, including patients with minor change (> or =25-<50% tumor shrinkage after treatment), was documented in 68.4% of cases and was independent of ER-beta levels or changes. ER-alpha levels were higher in tumors from patients in complete remission than in those from women achieving partial response or minor change compared with non-responsive patients (median expression values: 801 versus 516 versus 320 arbitrary units) and were consistently down-regulated by preoperative treatment. We conclude that in this elderly patient population with ER-alpha-positive tumors, ER-beta mRNA was neither predictive of response to preoperative toremifene nor provided additional information to the knowledge of ER-alpha mRNA levels, which, conversely, were directly correlated with likelihood of response.

Transcription and alternative splicing of telomerase reverse transcriptase in benign and malignant breast tumours and in adjacent mammary glandular tissues: implications for telomerase activity.

Telomerase activity was determined in 15 breast cancers, 24 benign breast lesions, and 36 breast tissues adjacent to benign or malignant tumours. A positive TRAP (telomeric repeat amplification protocol) signal was detected in 67% of carcinomas and 29% of benign tumours. In five of ten cases, non-invaded breast tissues adjacent to telomerase-positive carcinomas also displayed telomerase activity. Conversely, in peritumoural specimens adjacent to benign lesions, telomerase activity was never detected. To investigate the regulatory mechanisms of telomerase activity in breast tissues, the expression of telomerase subunits was assessed, as well as the presence of alternatively spliced variants of human telomerase reverse transcriptase (hTERT). The presence of the hTERT full-length transcript appeared necessary for telomerase activity in breast carcinomas. Specifically, all telomerase-positive carcinomas expressed the hTERT full-length message, together with different combinations of alternatively spliced variants, whereas in telomerase-negative cancers, the hTERT full-length transcript was not detectable, or its abundance was markedly lower than that of alternatively spliced variants. Results obtained in benign tumours and normal tissues surrounding carcinomas instead showed that the presence of hTERT full-length transcript was not sufficient to determine telomerase activity. These findings suggest that in non-neoplastic tissues there are other mechanisms that suppress telomerase activity downstream from hTERT transcription and mRNA splicing and that such mechanisms have been lost during neoplastic transformation.