Department of Experimental Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy
*E-mail: danila.coradini@istitutotumori.mi.it
Despite the numerous studies performed, the best timing of surgery for premenopausal patients with breast cancer remains a debated issue due to its controversial association with clinical outcome. In particular, a renewed interest has grown in the clinical aspects of the hypothesis that the hormonal milieu at the time of surgery may influence patient prognosis [1], with the luteal phase probably associated with a decreased risk of relapse. Also, disease recurrence and survival might be affected by the menstrual timing of ablative/additive endocrine manipulations, with a favorable outcome of women undergoing ovarian ablation plus tamoxifen treatment during the luteal phase [2].
Based on previous findings that aggressiveness and invasion-related markers tend to be overexpressed in primary tumors removed during the follicular phase [3], and on the hypothesis that during specific times of the menstrual cycle up-regulation of hormonally controlled genes might influence tumor cell shedding and survival, we investigated the expression of biological variables involved in cell cycle and apoptosis regulation (p53, p27kip1, Bcl-2, Bax) and angiogenesis [vascular endothelial growth factor (VEGF)] in breast cancers from 629 premenopausal women, as a function of the menstrual timing of surgery. All the women had a regular menstrual cycle not exceeding 36 days. The estrogen and progesterone receptor (ER, PgR) status of all tumors was biochemically determined. Expression of p53, p27kip1, Bcl-2 and Bax was immunohistochemically evaluated and VEGF immunoenzymatically measured.
Regardless of ER status, PgR and VEGF concentrations fluctuated during the menstrual cycle (Figure 1 and Table 1), with the highest values around day 11. This was probably due to the stimulatory effect of increasing plasma levels of estradiol, which, after binding ER, induced the synthesis of these two estrogen-related proteins. In the subsequent luteal phase, PgR and VEGF concentrations dramatically decreased. VEGF expression paralleled estradiol levels and increased again during the late luteal phase concomitantly with progesterone withdrawal. In contrast, expression of p27kip1, p53, Bcl-2 and Bax remained relatively stable, in agreement with previous results [4].
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Acknowledgements
This work was supported in part by grants from the Italian Association for Cancer Research (AIRC).
D. Coradini*, S. Veneroni, C. Pellizzaro & M. G. Daidone
Department of Experimental Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy (*E-mail: danila.coradini@istitutotumori.mi.it)
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