Journal
TOXICOLOGY AND APPLIED PHARMACOLOGY
Volume 364, Issue -, Pages 77-82Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.taap.2018.12.013
Keywords
Breast cancer; Tumor-associated macrophage; Hedgehog inhibitor; IL6
Categories
Funding
- National Fund [81273526, 81473268]
- Natural Science Foundation of Anhui Province [1308085MH145]
- Science and Technology Project of Anhui Province [1301042212]
- Special Scientific Research Fund for the Doctoral Program of Higher Education [20123420120001]
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Hedgehog (Hh) pathway hyperactivation has been observed in various tumors, including breast cancer, and Hh pathway inhibitors have demonstrated antitumor activity in breast cancer. The tumor microenvironment (TME) has been shown to play an important role in modulating cancer cell drug sensitivity, but the TME response to Hh pathway inhibitors is unclear. In the current study, we observed increased TME infiltration of macrophages in breast cancer tissue, and specifically, M2 polarized macrophages after neoadjuvant chemotherapy. Furthermore, we observed an enhanced tolerance to Hh pathway inhibitors in MDA-MB-231 cells after co-culturing with M2 macrophages. In addition, we demonstrated that Hh pathway inhibition significantly induced IL6 expression, and validated that the tolerance to Hh pathway inhibitors was IL6-dependent. This study demonstrates a role of macrophages in Hh pathway inhibition resistance and a role of macrophage-derived IL6 in this resistance of breast cancer cells to Hh inhibition. These data indicate that antagonizing IL6 together with Hh pathway inhibitors may be a novel therapeutic strategy for breast cancer.
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