Title

In vivo characterization of the Duffy Antigen Receptor for Chemokines (DARC) in the breast cancer microenvironment

Document Type

Conference Proceeding

Publication Date

7-1-2018

Publication Title

Cancer Res

Abstract

Chemokines are small inflammatory molecules that, in combination with their receptors, recruit lymphocytes to influence immune and inflammatory responses. This work specifically follows an atypical chemokine receptor, known as the Duffy Antigen Receptor for Chemokines (DARC). DARC is a non-signaling receptor able to bind both the CC and CXC chemokine classes, and mainly functions to regulate homeostatic levels of chemokines in circulation, and aid in chemokine transcytosis from sites of inflammation to mediate immune response. DARC serves as a portal of entry for the malaria-causing parasite Plasmodium vivax. In Sub-Saharan Africa, where malaria is endemic, a regulatory variant arose removing DARC expression from red blood cells (RBCs). This mutation, known as the Duffy-Null allele, was highly beneficial in this population, as removal of DARC from RBCs conferred immunity to Duffy-Null individuals. The Duffy-Null allele quickly rose to fixation in this population, and today recent decedents of Sub-Saharan Africans carry this allele. In the context of breast cancer (BCa) we are particularly interested in how Duffy-Null status impacts the tumor microenvironment. In clinic, we observe that pre-menopausal women of African descent have higher incidence rates of BCa, and that regardless of age, these women are disproportionately diagnosed with the most aggressive molecular subtype of BCa, triple-negative BCa. Knowing the important role that DARC plays in immune response, and that the Duffy-Null allele is prevalent in this population of women, we aim to investigate how Duffy-Null status impacts the tumor microenvironment in vivo through establishment of mouse models that depict Duffy-Null status in the BCa environment. To do this, we are using the C3(1)-TAg BCa transgenic mouse, alongside a DARC-KO mouse to characterize cancer progression and aggressiveness in BCa transgenic mice with varying global DARC expression. At 6 and 12 week time points, mice were sacrificed and the following information was obtained: total number of tumors, tumor location, tumor size and weight, and hematoxylin and eosin staining of tumor sections. Removal of DARC could lead to an excess of chemokines in the tumor microenvironment, promoting processes of tumor progression and metastasis, leading to the more aggressing tumor phenotypes we observe in women of African descent in clinic.

Volume

78

Issue

13

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