Autophagy facilitates the progression of ERα-positive breast cancer cells to antiestrogen resistance

Abstract

A major impediment to the successful treatment of estrogen receptor alpha (ERalpha)-positive breast cancer is the development of antiestrogen resistance. Tamoxifen, the most commonly used antiestrogen, exerts its pharmacological action by binding to ERalpha and blocking the growth-promoting action of estrogen-bound ERalpha in breast cancer cells. Tamoxifen treatment primarily induces cytostasis (growth arrest) and the surviving breast cancer cells commonly acquire tamoxifen resistance. Numerous clinically-relevant mechanisms of acquired antiestrogen resistance have been identified by in vitro studies. Our recent studies (Mol Cancer Ther 2008; 7:2977-87) now demonstrate that autophagy (also referred to as macroautophagy) is critical to the development of antiestrogen resistance. Under conditions of compromised autophagy, including treatments with pharmacological inhibitors and RNAi targeting of the beclin 1 gene, the cytotoxicity (death-inducing effects) of the antiestrogen 4-hydroxytamoxifen (4-OHT) was significantly increased. 4-OHT is an active metabolite of tamoxifen commonly used for in vitro studies. A step-wise drug selection protocol, using 4-OHT as the selecting drug, established antiestrogen-resistant breast cancer cell lines. Analysis of a representative resistant cell line showed an increased ability of the cells to sustain high levels of antiestrogen-induced autophagy without progression to death. Importantly, blockade of autophagosome function in the 4-OHT-treated, antiestrogen-resistant cells induced a robust death response. These data provide strong evidence that autophagy is a key mechanism of cell survival during antiestrogen challenge and progression to antiestrogen resistance. We discuss the potential benefit of blocking autophagosome function to significantly reduce the emergence of antiestrogen-resistant breast cancer cells.

Mechanisms associated with resistance to tamoxifen in estrogen receptor-positive breast cancer (Review)

“…Recent studies have demonstrated that autophagy (also referred to as macroautophagy) is critical to the development of anti-estrogen resistance (130). This pro-survival role for autophagy in anti-estrogen-treated breast cancer cells is consistent with one function of the autophagosomes, which is to recycle metabolites from degraded cellular constituents to support a basal level of cell maintenance under starvation conditions and OS, thus rendering it essential for cellular viability.…”

The Prolyl Isomerase Pin1 Induces LC-3 Expression and Mediates Tamoxifen Resistance in Breast Cancer

“…Autophagy is a key mechanism of cell survival in ER-positive breast cancer cells, resulting in the development of tamoxifen resistance (21). Also, antiestrogen resistance could be reduced by targeting autophagosome function, which is regulated by LC-3, Beclin-1, Atg-5, and Atg-12 (21)(22)(23), suggested that high Pin1 expression in tamoxifen-resistant MCF7 cells may enhance autophagy through increased expression of autophagy-related proteins, such as LC-3, to produce tamoxifen resistance. As expected, LC-3 levels were higher in tamoxifen-resistant MCF7 cells, and Pin1 overexpression produces the same expression patterns as tamoxifen-resistant cells, suggesting that Pin1 regulates tamoxifen resistance via enhanced LC-3 expression (Fig.…”

Elevated Beclin 1 expression is correlated with HIF-1α in predicting poor prognosis of nasopharyngeal carcinoma

“…41 Compromising autophagy by Beclin 1 inhibition or siRNA greatly increases the cytotoxicity of the antiestrogen 4-hydroxytamoxifen in breast cancer cells. 42 However, the opposite reaction of Beclin 1 to tumor therapy was also detected. In lung and breast cancer cells, inhibition of Beclin 1 results in radiation resistance, and overexpression of Beclin 1 potentiates the sensitivity of wild-type cancer cells to radiation.…”