Role of Bcl-2 in hormone-dependent endometrioid corpus cancer

A Mariani, MD, TJ Sebo, MD, PhD, MJ Webb, MD, GL Keeney, MD, T Lesnick, MS, KC Podratz, MD, PhD

Mayo Clinic, Rochester, MN United States

Aim: It has been suggested that bcl-2 is involved in the inhibition of apoptosis, favouring the acquisition of new genetic mutations and the subsequent development of metastases in breast cancer (Sierra et al. Int J Cancer 2000). Bcl-2 gene expression appears to be under hormonal control in the normal endometrium (Otsuki et al. Lancet 1994), and has been shown to correlate directly with hormone receptor positivity, endometrioid histology and low grade disease in endometrial cancer (Yamauchi et al. Int J Gynecol Pathol 1996; Zheng et al. Gynecol Oncol 1996). It is plausible that bcl-2 may have a role in suppressing apoptosis, thereby favouring the acquisition and accumulation of genetic alterations, in a subgroup of hormone-dependent endometrial cancers. The aim of this study was to evaluate the role of bcl-2 in hormone-dependent endometrial carcinogenesis. Method: A previously reported case-cohort designed study population of 125 hysterectomy specimens subjected to immunohistochemical staining for bcl-2 was analyzed. Bcl-2 cytoplasmic staining was visually interpreted as negative (bcl-) vs positive (bcl+). ER and PR levels were quantitated on fresh tissue using a dextran-coated charcoal assay (fmol/mg of protein). Wilcoxon Rank Sum Tests and chi-square analyses were used for weighted statistics. Results: Non-endometrioid histology was documented in 18% of the specimens, histologic grade 3 in 29%, and bcl+ in 73%. Mean levels of ER and PR were 254 fmol/mg and 434 fmol/mg, respectively. Bcl-2 expression correlated (borderline significance) with endometrioid histology (p=0.08). Mean ER and PR levels were 89 fmol/mg and 190 fmol/mg, respectively, in bcl- tumors, compared to 271 fmol/mg (p<0.01) and 419 fmol/mg (p<0.01) in bcl+ tumors. Analyzing the entire population, bcl-2 expression was not significantly associated with the presence of extrauterine disease. However, considering only patients with grade 1 and 2 endometrioid histology (disease generally considered hormone dependent) 23% of bcl+ patients had extrauterine disease and 13% had positive lymph nodes, compared to 7% with extrauterine disease (p=0.02) and 0% positive nodes (p=0.053) in bcl- patients. Conclusion: Bcl-2-mediated inhibition of apoptosis may be an important step in the acquisition of additional genetic mutations and the subsequent development of metastases in low grade endometrioid hormone-dependent endometrial cancers.

KEY WORDS: estrogen and progesterone receptors, apoptosis, endometrial cancer.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Apoptosis - Molecular Mechanisms.