ESTROGEN-RECEPTORS - NEW PERSPECTIVES IN BREAST-CANCER MANAGEMENT

The imbalance between proliferative and differentiative estrogenic eff ect, caused by quantitative and qualitative alteration of the estrogen receptor (ER) expression, may play a determinant role in mammary neop lastic transformation. Our studies demonstrate that ER levels are sign ificantly higher in human mammary neoplastic tissues when compared to perineoplastic tissues and that increased ER expression is associated with ER gene hypomethylation. During progressive multifactorial carcin ogenesis, ER overexpression may represent an early step in neoplastic transformation. In fact, high levels of ER represent good markers of d ifferentiation and can predict the likelihood of benefiting from anti- estrogen therapy. Nevertheless, about 35% of ER-positive breast cancer s are resistant to endocrine therapy and 10% of ER-negative tumors beh ave as hormone-sensitive tumors. Recent studies on ER mRNA variants, w hich naturally occur in human breast tumors, demonstrated mutations, d eletions and alternative splicings, yielding deletions of exons 3, 4, 5 and 7. ER variants exhibited altered functions or changed the respon siveness to hormonal therapy. Analysis of these variants could be a us eful parameter to better predict tumor responsiveness to anti-estrogen therapy. Recently, a regain of hormonal responsiveness by ER-negative breast cancer cells has been reported following ER gene transfection. However, estradiol treatment inhibits rather than stimulates cell gro wth as well as the metastatic and invasive potential of the ER gene tr ansduced cells. Transfer of the ER gene may be considered as a new the rapeutic approach in the management of hormone-independent breast canc er.