Type Ⅱ Interleukin-4 Receptor Activation in Basal Breast Cancer Cells Promotes Tumor Progression

Abstract

Interleukin 4 (IL4) is a Th2 cytokine initially discovered as a B-lymphocyte proliferative factor. In the context of cancer IL4 is largely studied for its role in promoting an immunosuppressive tumor microenvironment. The type Ⅱ IL4 receptor is expressed predominantly by non-hematopoietic cells, and has been shown to be expressed in a number of cancers including breast, prostate, colorectal and pancreatic cancers. Relatively little is known about the consequences of IL4 signaling through the type Ⅱ and how it may contribute to tumor progression. In this thesis we explore the role of type Ⅱ IL4 receptor expressed in basal breast cancer, and how signaling through the type Ⅱ supports proliferation and growth of basal breast cancer. In chapter Ⅰ I present an introduction on the contributions of metabolism to cancer progression, the biology of breast cancer clinical subtypes, and a brief introduction to the biology of IL4 and its receptors. In chapter Ⅱ, using various in vitro methods I demonstrate that type Ⅱ signaling increases glucose metabolism, and histone acetylation in basal breast cancer. This increased histone acetylation and glucose uptake induces expression of genes associated with proliferation, and survival of breast cancer cells such as BCL2, and CCND2. In chapter Ⅲ I further explore how IL4 impacts metabolic regulation of basal breast cancer and show that some effects are temporally regulated. In chapter Ⅳ using a humanized mouse model that targeting the type Ⅱ IL4 receptor using a dominant negative mutant of IL13 attenuates metastatic colonization of basal breast cancer in vivo.