After decades of research, breast cancer still remains the leading cause of cancer mortality in women. The majority of these breast cancer deaths is due to metastasis, which is still poorly understood and incurable. Recently it has been appreciated that the tumor microenvironment plays a significant role in both tumor progression and response to chemotherapy. However, its role in metastasis formation is still largely unclear. In this project we focus on the role of the inflammatory microenvironment on metastatic breast cancer and chemotherapy responsiveness.
In our research we make use of the conditional K14cre;EcdF/F;P53F/F breast cancer mouse model that spontaneously develops mammary tumors resembling human invasive lobular carcinomas (ILC). These tumors reside in an inflammatory microenvironment which is characterized by expression of inflammatory cytokines resulting in infiltration of large numbers of immune cells. About 50% of K14cre;EcdF/F;P53F/F animals develop micrometastases in distant organs like lung, lymph node and spleen, however they do not succumb to metastatic disease. We hypothesize that the inflammatory tumor microenvironment plays a role in breast cancer metastasis formation and possibly in chemotherapy efficacy. Exploiting the K14cre;EcdF/F;P53F/F model, mouse ILC (mILC) pieces are transplanted into the 4th mammary gland of wild type recipient mice. Tumors are allowed to grow to a specific size upon which a mastectomy is performed mimicking the clinical situation. Mice are sacrificed as soon as they show clinical signs of metastatic disease. This transplantable model allows us to study the effect of the microenvironment on breast cancer metastasis and chemotherapy responsiveness in two distinct settings: a neo-adjuvant setting (treatment targeting primary tumor growth) and an adjuvant setting (treatment after mastectomy specifically targeting metastatic outgrowth). Using this model we set out to study the effect of the inflammatory microenvironment in breast cancer metastasis formation and chemotherapy responsiveness. We found that neo-adjuvant chemotherapy treatment resulted in a significant delay of primary tumor growth. As a result, metastasis-free survival was significantly increased compared to controls. Also adjuvant chemotherapy treatment resulted in a survival benefit compared to controls. We are currently studying the effect of inflammatory cytokine inhibition on chemotherapy responsiveness and formation of distant metastases. Therefore we are analyzing different populations of immune cells in the inflammatory tumor microenvironment by flow cytometry. Subsequently, we are looking into the pattern of metastasis formation throughout the body. This research is funded by the Dutch Cancer Society; 2011-5004.
Citation Format: Kelly Kersten, Metamia Ciampricotti, Chris W. Doornebal, Cheei-Sing Hau, Seth B. Coffelt, Karin de Visser. The impact of the inflammatory microenvironment on breast cancer metastasis and chemotherapy responsiveness. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr A96.