Robert Clarke

Social isolation induces autophagy in the mouse mammary gland: link to increased mammary cancer risk

Social isolation is a strong predictor of early all-cause mortality and consistently increases breast cancer risk in both women and animal models. Because social isolation increases body weight, we compared its effects to those caused by a consumption of obesity-inducing diet (OID) in C57BL/6 mice. Social isolation and OID impaired insulin and glucose sensitivity. In socially isolated, OID-fed mice (I-OID), insulin resistance was linked to reduced Pparg expression and increased neuropeptide Y levels, but in group-housed OID fed mice (G-OID), it was linked to increased leptin and reduced adiponectin levels, indicating that the pathways leading to insulin resistance are different. Carcinogen-induced mammary tumorigenesis was significantly higher in I-OID mice than in the other groups, but cancer risk was also increased in socially isolated, control diet-fed mice (I-C) and G-OID mice compared with that in controls. Unfolded protein response (UPR) signaling (GRP78; IRE1) was upregulated in the mammary glands of OID-fed mice, but not in control diet-fed, socially isolated I-C mice. In contrast, expression of BECLIN1, ATG7 and LC3II were increased, and p62 was downregulated by social isolation, indicating increased autophagy. In the mammary glands of socially isolated mice, but not in G-OID mice, mRNA expressions of p53 and the p53-regulated autophagy inducer Dram1 were upregulated, and nuclear p53 staining was strong. Our findings further indicated that autophagy and tumorigenesis were not increased in Atg7(+/-) mice kept in social isolation and fed OID. Thus, social isolation may increase breast cancer risk by inducing autophagy, independent of changes in body weight.

Chapter 17 – Autophagy, Inflammation, and Breast Cancer Risk

Abstract Breast cancer is the most prevalent cancer in women, with more than 246,000 new cases diagnosed annually. Based upon receptor profiling, breast cancer can be classified into estrogen receptor (ER) positive, human epidermal growth factor-2 receptor (HER2) overexpressing, or triple negative (TN) that are ER negative, progesterone receptor negative, and HER2 normal. Targeted therapy options, such as selective ER modulators or aromatase inhibitors for ER+ breast cancer, or HER2-targeted antibodies and EGFR inhibitors for HER2-overexpressing breast cancers, improve overall survival rates. TN breast cancers are limited to cytotoxic chemotherapeutic options. Unfortunately, many of these tumors develop resistance to treatments, which limit the curative potential of these therapies. Autophagy, a cellular process of “self-eating,” is implicated as a possible contributor to therapy resistance in breast cancer. Autophagy plays an important role in inflammation and immune responses, which may impact breast cancer risk and therapeutic responsiveness.

Chapter 7 – Blockage of Lysosomal Degradation Is Detrimental to Cancer Cell Survival: Role of Autophagy Activation

Autophagy is a major catabolic process used by cells to remove superfluous or damaged proteins and organelles. In the final stages of autophagy, acidic organelles (lysosomes) act to degrade autophagic cargo and to facilitate their recycling. Little is known about how cancer cells undergoing autophagy, often as a consequence of stress, respond when lysosomal function is blocked. To elucidate this mechanism, several recent studies report that lysosomes and their hydrolytic proteases (cathepsins) play a critical role in autophagy and subsequent cancer progression. Our studies in breast cancer suggest that inhibition of cathepsins D and L using the BH3-mimetic, obatoclax, is effective in reducing the cell density of anti-estrogen sensitive and resistant breast cancer cells. Furthermore, blockage of cathepsin protein expression with obatoclax leads to the accumulation of autophagic vacuoles and impairs the ability of cells to use degraded material to restore homeostasis. While cancer cells are dependent on effective lysosomal function, neoplastic transformation induces changes in lysosomal volume, number, and protease activity. Recent reports suggest that pro-oncogenic changes render cancer cells more susceptible to lysosomal-associated death pathways. A number of distinct stimuli have been shown to permeabilize the lysosomal membrane, leading to the release of hydrolases into the cytosol and ultimately cell death. Thus, changes in cathepsin and lysosomal membrane permeabilization (LMP) regulation during cancer cell progression suggest that strategies targeting this cellular compartment may be exploited to improve outcomes for cancer patients.