Expression of estrogen receptor β increases integrin α1 and integrin β1 levels and enhances adhesion of breast cancer cells

Abstract

Estrogen effects on mammary gland development and differentiation are mediated by two receptors (ERalpha and ERbeta). Estrogen-bound ERalpha induces proliferation of mammary epithelial and cancer cells, while ERbeta is important for maintenance of the differentiated epithelium and inhibits proliferation in different cell systems. In addition, the normal breast contains higher ERbeta levels compared to the early stage breast cancers, suggesting that loss of ERbeta could be important in cancer development. Analysis of ERbeta-/- mice has consistently revealed reduced expression of cell adhesion proteins. As such, ERbeta is a candidate modulator of epithelial homeostasis and metastasis. Consequently, the aim of this study was to analyze estrogenic effects on adhesion of breast cancer cells expressing ERalpha and ERbeta. As ERbeta is widely found in breast cancer but not in cell lines, we used ERalpha positive T47-D and MCF-7 human breast cancer cells to generate cells with inducible ERbeta expression. Furthermore, the colon cancer cell lines SW480 and HT-29 were also used. Integrin alpha1 mRNA and protein levels increased following ERbeta expression. Integrin beta1-the unique partner for integrin alpha1-increased only at the protein level. ERbeta expression enhanced the formation of vinculin containing focal complexes and actin filaments, indicating a more adhesive potential. This was confirmed by adhesion assays where ERbeta increased adhesion to different extracellular matrix proteins, mostly laminin. In addition, ERbeta expression was associated to less cell migration. These results indicate that ERbeta affects integrin expression and clustering and consequently modulates adhesion and migration of breast cancer cells.

Nuclear SIPA1 activates integrin β1 promoter and promotes invasion of breast cancer cells

“…Indeed, when we overexpressed SIPA1 in MCF7 cells, we found that it did not affect integrin β1 promoter activity (Data not shown), which should be due to the relatively high estrogen receptor expression levels in MCF7, as it's been reported that estrogen receptor-β could regulate ITGB1 expression in breast cancer cells. 47 In addition, we also assayed the localization of SIPA1 in HeLa cells and found that both cytoplasmic and nuclear SIPA1 increased markedly upon transfection with SIPA1, with the level of nuclear SIPA1 being somewhat higher than that of cytoplasmic SIPA1. However, overexpressed SIPA1 did not affect integrin β1 promoter activity in HeLa cells (Data not shown), suggesting that regulation of SIPA1 on integrin β1 promoter is cell-type dependent.…”

Important role of integrins in the cancer biology

“…Breast cancer cell-derived thrombopondin-1 has the potential to promote angiogenesis [89]. ER-β expression is associated to less cell migration because its expression level is reduced in cancer cells by affecting integrin expression and clustering and consequently modulates adhesion and migration of breast cancer cells [90].…”

Emerging functional roles of nuclear receptors in breast cancer

“…Overexpression of ESR2 leads to reduced cell growth and mobility and ESR2 was reported to upregulate E-cadherin (Zhou et al 2015), integrin alpha1, integrin beta1 and enhance the formation of vinculin-containing focal complexes and actin filaments (Lindberg et al 2010), which consequently strengthens cell adhesion and reduces migration and invasion.…”