Autophagy and endocrine resistance in breast cancer

Abstract

The American Cancer Society estimates that over 200,000 new breast cancer cases are diagnosed annually in the USA alone. Of these cases, the majority are invasive breast cancers and almost 70% are estrogen receptor-α positive. Therapies targeting the estrogen receptor-α are widely applied and include selective estrogen receptor modulators such as tamoxifen, a selective estrogen receptor downregulator such as Fulvestrant (Faslodex; FAS, ICI 182,780), or one of the third-generation aromatase inhibitors including letrozole or anastrozole. While these treatments reduce breast cancer mortality, many estrogen receptor-α-positive tumors eventually recur, highlighting the clinical significance of endocrine therapy resistance. The signaling leading to endocrine therapy resistance is poorly understood; however, preclinical studies have established an important role for autophagy in the acquired resistance phenotype. Autophagy is a cellular degradation process initiated in response to stress or nutrient deprivation, which attempts to restore metabolic homeostasis through the catabolic lysis of aggregated proteins, unfolded/misfolded proteins or damaged subcellular organelles. The duality of autophagy, which can be either pro-survival or pro-death, is well known. However, in the context of endocrine therapy resistance in breast cancer, the inhibition of autophagy can potentiate resensitization of previously antiestrogen resistant breast cancer cells. In this article, we discuss the complex and occasionally contradictory roles of autophagy in cancer and in resistance to endocrine therapies in breast cancer.

Figure 1. Cellular pathway of autophagy

The PI3K complex mediates the initiation of the phagophore membrane, enveloping labeled cytosolic proteins organelles and fat. mTOR and Bcl-2 can inhibit the initiation of autophagy. The Atg12-Atg5-Atg16 complex, LC3 and the transmembrane Atg9 are recruited to the phagophore and are necessary for elongation of the double membrane. Lysosomes fuse with the autophagosome, creating the autolysosome. The resulting products of the catalytic degradation process are transported to the cytosol and recycled. LC: Light chain-3.

Figure 2. Effect of the unfolded protein response on autophagy

The unfolded protein response can activate autophagy through two distinct mechanisms. PERK activation leads to phosphorylation of eIF2α, resulting in increased ATF4 transcription. ATF4 promotes the transcription of Atg12, resulting in increased autophagy. Another mechanism of unfolded protein response-modulating autophagy is through activation of IRE1. IRE1 activates JNK, leading to the subsequent phosphorylation of Bcl-2. Bcl-2 phosphorylation prevents its binding to beclin-1, thereby promoting autophagy. ATF: Activating transcription factor; IRE1: Inositol requiring enzyme-1; PERK: PKR-like endoplasmic reticulum kinase.