Advisory Committee Chair
Douglas R Hurst
Date of Award
Degree Name by School
Doctor of Philosophy (PhD) School of Health Professions
Curative approaches for metastatic breast cancer remain elusive. Adiponectin is the most abundant of the adipocyte-secreted adipokines, and there is recent interest in development of adiponectin-based therapies for this disease. Yet, while multiple epidemiological studies have indicated that low levels of circulating plasma adiponectin portend poorer prognosis, recent work has reported that elevated adiponectin expression in breast tissue correlates with advanced disease. Further, isoform-specific roles of this molecule are not well understood. Thus, the overarching purpose of this work was to elucidate how adiponectin isoforms contribute to the microenvironmental regulation of the early steps of breast cancer metastasis. We show that the globular adiponectin isoform (gAd) may promote development of metastatic disease in part by acting directly on invasive tumor cells to induce autophagy. In a human metastatic breast cancer cell line, gAd enhanced invasive morphology, invasion (91%; p < 0.001), and migration (222%; p < 0.05) in a manner similar to rapamycin, an established autophagy inducer. Full length adiponectin (fAd) had no significant effect. In support, gAd, but not fAd, increased LC3B-II expression and the number of intracellular LC3B puncta, markers of autophagic induction. And, silencing ATG7, an essential autophagy gene, blunted the effects of gAd on promoting invasion, suggesting that autophagic induction contributes to gAd-induced increases in metastatic potential. Probing these results, we explored whether distinct breast cancer cell populations have increased autophagic potential that leads to increased ability to metastasize. Indeed, autophagy can promote cell survival in response to stress, and only a select few tumor cells survive the stresses inherent in the metastatic process. We show that the cell populations that were most responsive to autophagic induction were those that best weathered nutrient deprivation, one stress encountered throughout the metastatic cascade. Therefore, it is possible that certain breast cancer cell populations also differ in their response to autophagic induction by gAd, affecting gAd-induced invasion. This work is timely considering not only the preclinical development of adiponectin receptor agonists, but also the clinical use of autophagy modulators as therapeutic strategies for reducing breast cancer’s heavy mortality burden.
Libby, Emily, "Linking Adiponectin and Autophagy in the Regulation of Breast Cancer Metastatic Potential" (2015). All ETDs from UAB. 2284.