Abstract 4859: The role of LPAR1 and fibrosis in breast cancer metastasis
Authors: Brooks Danielle L. , Wakefield Lalage , Steeg Patricia 
Published: July 2017

Tumor metastasis is a complex process in which tumor cells disseminate from the primary tumor to colonize distant organ sites. The majority of breast cancer related deaths are from metastatic disease, in part due to acquired resistance to chemotherapies. Aberrant tumor microenvironment often resembles fibrotic lesions where dysregulated cell signaling pathways alter tissue architecture and promote chronic inflammation. In fact, multiple studies have demonstrated a positive link between cancer metastasis and fibrosis, a condition characterized by increased activated fibroblasts (defined as αSMA positive) and extracellular matrix (EMC) such as collagen 1 secretion. Lysophosphatidic acid (LPA) is a signaling molecule that activates a family of G-protein coupled LPA receptors (LPARs) in both metastasis and fibrosis. Specifically, LPAR1 is highly expressed in metastatic breast cancer cell lines, and its activation is involved in the colonization and proliferation of cancer cells during the metastatic process. Our previous data have shown that inhibition of LPAR1 reduced the metastatic potential of breast cancer cells in vitro and in vivo. We sought to further study the relationship between metastasis, fibrosis and LPA signaling using mouse models of metastatic breast cancer. First, we investigated the extent to which metastasis is accompanied by fibrosis by utilizing 11 spontaneous mouse tumor models of metastatic breast cancer. Mouse lung sections were stained with either αSMA, collagen 1, or Masson’s trichrome (pan collagen fiber stain) followed by Ashcroft scoring. To evaluate whether targeting the observed fibrosis therapeutically could prevent metastasis, mice were injected intravenously with the breast cancer cell line MDA-MB-231T followed by randomization to treatment with either Nintedanib or Pirfenidone (two FDA approved drugs for idiopathic pulmonary fibrosis, IPF). Separately, mice were also treated with doxorubicin or paclitaxel, both of which are used clinically in treating metastatic disease. We found that fibrosis occurred in the majority of the mouse tumor models examined (9 out of 11), although the extent of fibrosis was heterogeneous across models. Treatment of lung metastases with IPF drugs alone, however, did not show efficacy in reducing metastatic burden. Interestingly, we observed that while treatment of lung metastases with chemotherapy reduced metastasis, it significantly increased the amount of fibrosis observed compared to vehicle treated mice. This finding is significant as most patients diagnosed with breast cancer will receive at least one round of chemotherapy in the course of treatment. Therefore, further studies will look to evaluate whether targeting fibrosis with LPAR1 or LPA inhibitors is more effective when given concurrently or post chemotherapy treatment as a means to decrease overall metastatic burden.

Citation Format: Danielle L. Brooks, Lalage Wakefield, Patricia Steeg. The role of LPAR1 and fibrosis in breast cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4859. doi:10.1158/1538-7445.AM2017-4859