Clonal selection in tamoxifen resistance.

摘要

The selective estrogen-response modulator (SERM), tamoxifen, is the most commonly used adjuvant treatment for postmenopausal women with early-stage estrogen receptor-CX (ER) positive breast cancer. Despite the relative safety and significant anti-neoplastic and chemopreven-tive activities of tamoxifen, many initially responsive breast tumors develop resistance and ultimately recur. Tamoxifen resistance can be classified into two categories: intrinsic or acquired. ER-OC expression is maintained at detectable levels in the majority of the tumors with acquired resistance. In these tumors, ER continues to regulate tumor proliferation. Twenty percent of patients who relapse on tamoxifen respond to the pure ER-antagonist, fulves-trant, or to aromatase inhibitors. Thus far, mechanisms of endocrine resistance in ER positive breast cancer include: (1) loss of ER expression by methylation and expression of truncated isoforms of ER-OC and ER-beta, (2) post-translational modifications of ER-OC, (3) increased API activity and deregulation of ER co-activators, (4) increased receptor tyrosine kinase signaling leading to the activation of the MAPK and PI3K pathways, and (5) deregulation of the cell cycle and apoptotic machinery. Thus, although many underlying molecular events that confer resistance are known, a unifying theme is yet to be revealed.