Role of Estrogens and Their Receptors in Adhesion and Invasiveness of Breast Cancer Cells

Abstract

Estrogen receptors (ERs) are overexpressed in human breast cancers (BCs) and associated with differentiated tumors and with a more favorable prognosis. Paradoxically, ERs mediate the mitogenic action of estrogens in human BC cells and the efficacy of antiestrogens in adjuvant therapy of primary tumors. The exact mechanism underlying the ER protection against cancer progression to metastasis remains to be investigated. Herein, we show that ERs decrease invasiveness of BC cells. Detailed studies revealed that the unliganded and the E2-activated ERs decrease cancer cell invasion in vitro through two distinct mechanisms. In the presence of ligand, ERalpha inhibits invasion through a mechanism requiring the functional ERalpha domains involved in the transcriptional activation of target genes. Moreover, using different approaches, we found that cell-cell contacts were markedly increased by 17beta-estradiol (E2) treatment and decreased by the pure antiestrogen, ICI182,780. This cell-cell adhesion was associated with an increase of the major intercellular junctions, desmosomes. Conversely, in the absence of ligand, ERalpha also inhibits invasion through a distinct mechanism involving protein-protein interaction with the region of the first zinc finger of ERalpha. The relationship of these data with clinical studies and their potential therapeutic consequences will be discussed.

RETRACTED ARTICLE: Regulation of estrogen receptor signaling in breast carcinogenesis and breast cancer therapy

“…The presence of ERα is a favorable prognostic marker associated with less invasive tumors, whereas tissues that are negative for ERα tend to be more aggressive. Introduction of ERα into ERα-negative breast cancer cells attenuates the aggressive cancerous phenotype in vitro [92,93]. Deregulation of ERα-coregulator signaling can lead to the aberrant expression of Snail resulting in the loss of expression of E-cadherin and invasive growth.…”

Association of estrogen receptor α gene PvuII and XbaI polymorphisms with non-small cell lung cancer

“…ERs reportedly inhibit proliferation and invasion of breast and lung cancer cells (7,28). Extranuclear forms of ER play a role in promoting downstream signaling for hormone-mediated proliferation and survival of breast as well as lung cancers and offer a new target for anti-tumor therapy (22).…”

“…However, regarding the association of the ER-α gene polymorphisms with non-small cell lung cancer, our results were based on a relatively modest sample size. The biological pathway for PvuII and XbaI that may affect oncogenesis remains unknown, although it is known that the intronic polymorphism of the ER-α gene may affect its protein synthesis and function as a modulator of the ligand estrogen (7,41). Moreover, with the exception of the ER-α PvuII and XbaI polymorphisms, there may also be numerous confounding factors between the groups, such as smoking and family histories and occupational exposures.…”

“…Findings of a previous study indicated that ER-β may not have the same physiological function as ER-α but may instead play a cofunctional role that is dependent upon the presence of ER-α (5). ER and the ER-regulated progesterone receptor are of special interest as their protein levels are always elevated in premalignant and malignant cancer cells (6,7). ERs are overexpressed in human breast cancers and associated with differentiated tumors and with a more favorable prognosis (7).…”

“…ER and the ER-regulated progesterone receptor are of special interest as their protein levels are always elevated in premalignant and malignant cancer cells (6,7). ERs are overexpressed in human breast cancers and associated with differentiated tumors and with a more favorable prognosis (7). The ER is regarded as one of the significant prognostic factors for breast and lung cancers (8)(9)(10).…”