Abstract 5178: Chitinase-3-like-1 (CHI3L1) expressed during allergic pulmonary inflammation alters lung microenvironment accelerating breast cancer metastasis

Abstract

Abstract Metastasis is the primary cause of mortality in women diagnosed with breast cancer. Metastasis to the lungs is greater in patients with pulmonary inflammatory illnesses, such as asthma. However, it is largely unknown how pulmonary inflammation impacts mammary tumor growth. Our laboratory has established a novel breast cancer model in which mice are induced with allergic pulmonary inflammation prior to mammary tumor implantation. In this study, we are determining how preexisting allergen-induced inflammation changes the pulmonary microenvironment to exacerbate tumor metastasis. Our studies have shown that pre-existing pulmonary inflammation increases the growth and metastasis of breast cancer cells. In the lungs of allergic tumor bearing mice, we found that sustained tissue injury resulting from pulmonary inflammation promoted infiltration of immune cells, collagen production, and enlargement of smooth muscle. In addition, we found high levels of a glycoprotein known as chitinase-3-like-1 protein (CHI3L1) in circulation and in lung tissue. We and others have reported that CHI3L1 is correlated with poor prognosis and decreased survival in breast cancer patients. In addition, we determined that myeloid derived cells from the lungs of allergic mice produced higher amounts of CHI3L1 compared to controls. Increases in CHI3L1 expression have been correlated with adverse effects on lung architecture through an increased deposition of collagen, smooth muscle actin and extracellular matrix proteins. Thus, we hypothesize that CHI3L1 expression in the lungs of mice with allergic pulmonary inflammation may alter the lung architecture and accelerate breast cancer metastasis. We assessed myeloid cell populations in the lungs of allergic mice and found higher levels of monocytes CD11b+Ly6C+Ly6G-, granulocytes CD11b+Ly6G+Ly6C-, and macrophages CD11b+F4/80+Ly6G-. These subpopulations were further increased in 4T1 tumor bearers with allergic pulmonary inflammation. Additionally, we show that CHI3L1 knockout tumor bearers with allergic pulmonary inflammation had decreased myeloid cells, dampened inflammation in the lungs, and a significant reduction in tumor volume and metastasis compared to controls. These changes may be driving the establishment of a premetastatic milieu in the lungs and aiding in the continued support of metastatic foci. Understanding the role of allergen induced CHI3L1 in tumor bearers and its effects on the pulmonary microenvironment could result in targeted therapies for breast cancer. Citation Format: Nathalia Gazaniga, Camilla S. Castro, Stephania Libreros, Ramon Garcia-Areas, Vijaya Iragavarapu-Charyulu. Chitinase-3-like-1 (CHI3L1) expressed during allergic pulmonary inflammation alters lung microenvironment accelerating breast cancer metastasis. [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 5178. doi:10.1158/1538-7445.AM2015-5178