Abstract 989: Regulation of metastatic potential through adiponectin-stimulated induction of autophagy (2015)

Abstract Each year, an unacceptable number of deaths occur in women because of the lack of curative approaches for metastatic breast cancer. Some of the key regulators of breast cancer progression are molecules within the tumor microenvironment including adipokines, a broad array of autocrine-, endocrine-, and paracrine-acting bioactive molecules secreted by adipocytes. Adiponectin is one of the most abundant adipokines and, while multiple widely cited 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 is, in fact, correlated with more advanced disease. Thus, the purpose of this work is to better understand how adiponectin in breast tissue acts directly on tumor cells to regulate the early steps of breast cancer metastasis. Our hypothesis is that adiponectin alters metastatic potential of breast cancer cells via induction of autophagy. To begin to test this premise, we discerned the effect of globular versus full-length adiponectin on invasive and migratory phenotypes of a human metastatic breast cancer cell line (MDA-MB-231). In transwell assays with and without Matrigel, globular adiponectin increased invasion (91%; p &lt; 0.001) and migration (222%; p &lt; 0.05) compared to untreated cells, whereas full length adiponectin had no significant effect. Rapamycin, an established autophagy inducer, elicited effects similar to globular adiponectin (increase of 210%; p &lt; 0.001 in invasion and 238%; p &lt; 0.05 in migration). Likewise, three-dimensional growth in Matrigel revealed that cells treated with globular adiponectin and rapamycin developed extended spikes indicative of a more invasive phenotype, whereas those treated with full-length adiponectin maintained a less invasive grape-like structure. Neither adiponectin isoform altered proliferation. Biochemical assays of autophagic induction supported these observations, demonstrating increases in LC3B-II expression (immunoblot) and in the number of intracellular LC3B puncta (immunofluorescence) upon treatment with globular, but not full-length, adiponectin. Together, these results suggest a plausible model linking a specific adiponectin isoform with induction of autophagy to stimulate breast cancer metastasis. Our findings will advance the field by revealing distinct, novel roles for key microenvironmental regulatory molecules, potentially opening up new avenues for therapeutic development. This work is timely considering recent interest in adiponectin and adiponectin receptor agonists as therapeutic strategies. In addition, noting that an aberrant level of adiponectin is a putative mechanism linking obesity to poor breast cancer prognosis and metastasis, our results may provide mechanistic insight to guide lifestyle interventions that will reduce breast cancer's heavy morbidity and mortality burden. Citation Format: Emily Falk Libby, Jianzhong Liu, Monica J. Lewis, Andra R. Frost, Wendy Demark-Wahnefried, Douglas R. Hurst. Regulation of metastatic potential through adiponectin-stimulated induction of autophagy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 989. doi:10.1158/1538-7445.AM2015-989