Autophagy in breast cancer and its implications for therapy

Abstract

Autophagy is an evolutionarily conserved process of cellular self-digestion that serves as a mechanism to clear damaged organelles and recycle nutrients. Since autophagy can promote cell survival as well as cell death, it has been linked to different human pathologies, including cancer. Although mono-allelic deletion of autophagy-related gene BECN1 in breast tumors originally indicated a tumor suppressive role for autophagy in breast cancer, the intense research during the last decade suggests a role for autophagy in tumor progression. It is now recognized that tumor cells often utilize autophagy to survive various stresses, such as oncogene-induced transformation, hypoxia, endoplasmic reticulum (ER) stress and extracellular matrix detachment. Induction of autophagy by tumor cells may also contribute to tumor dormancy and resistance to anticancer therapies, thus making autophagy inhibitors promising drug candidates for breast cancer treatment. The scientific endeavors continue to define a precise role for autophagy in breast cancer. In this article, we review the current literature on the role of autophagy during the development and progression of breast cancer, and discuss the potential of autophagy modulators for breast cancer treatment.

Keywords: Autophagy; ER stress; apoptosis; breast cancer; cancer therapy; hypoxia; metabolism; metastasis; transformation; tumor microenvironment.

Figure 1

Role of autophagy in breast cancer initiation and progression. Autophagy plays an important role in several aspects of breast cancer, such as tumor initiation or transformation of mammary epithelial cells, resistance of breast cancer cells to detachment-induced cell death facilitating metastatic spread and maintenance of epithelial phenotype to possibly promote tumor growth at secondary sites. While excessive self-eating can promote death, low levels of autophagy activated in response to cellular stress is believed to promote resistance of breast cancer cell to chemotherapy, radiation and targeted therapy in most settings. Another area where autophagy is gaining importance is in the heterotypic signaling between the mammary tumor and stroma to sustain the growth of cancer cells.