Abstract P6-05-02: Targeting vesicular trafficking machinery for breast cancer therapeutics

Abstract

Abstract The Rab GTPase family is a key regulator of vesicular import, transport and export. Deregulation of vesicular trafficking promotes undesirable intercellular cross talk via exosomes that contribute to cancer pathophysiology. Preclinical and clinical studies underscore a role for exosomes and their cargo in breast cancer development, progression, metastasis, and resistance to therapy. While many studies have approached the role of exosomes in cancer pathophysiology, the 'rules' governing their production and cargo sorting represents a major unexplored gap in knowledge. Exosomes arise from internal budding of specific endosomal compartments. Rab11 GTPase family members comprised of Rab11a, Rab11b and Rab25 are critical regulators of endocytic cargo trafficking specifically of apical and recycling endosomes. Previously, our lab has shown that Rab25 is amplified and contributes to oncogenesis in both ovarian and Luminal B breast cancers. However, Rab25 is lost and when re-expressed ectopically, it inhibits invasion and migration in Claudin Low tumors suggesting a cell-lineage and context dependent function. Importantly, while in Luminal B cancer, Rab25 and its downstream effector RCP (Rab coupling protein), collaborate in driving oncogenesis, in Her2+ cancers, RCP expression is protective. Further our group recently uncovered the presence of a stroma enriched “reactive protein signature” in ER+/Her- group that is indicative of good outcome for patients. Indeed, many of the “reactive signature” proteins are reported in exosomal cargo by others. Taking together, our ongoing study utilizes a panel of breast cancer cell lines representing ER+ve/Her2+; ER+/Her-, ER-/Her2+, and ER-/Her- to evaluate the role of Rab11 family in modulating vesicular trafficking that alters the exosome biology and how that may contribute to tumor- stroma communications. Our preliminary results show that indeed over expression of Rab25 differentially alters size and number of extracellular vesicles in Luminal B cancers when compared to the Claudin Low subtype. Using a novel class of peptides that interrupt the cellular functions 25, we are investigating if Rab25 expression can be associated with an exosomal cargo profile in each subtype of breast cancer, which could then serve as a biomarker for tumor-stroma interaction. Citation Format: Mitra S, Vykoukal J, Jeong K, Mills G. Targeting vesicular trafficking machinery for breast cancer therapeutics [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-05-02.