Most breast cancer deaths result from the emergence of metastatic spread of tumor cells. While the use of cytotoxic cancer therapies allows for the near complete eradication of malignant breast cells, relapse occurs in many cases. Surprisingly, these relapsed cancer cells often display more aggressive phenotypes than the primary tumors they derive from, in agreement with the recent demonstration that exposure to chemotherapy can favor invasiveness and metastatic features in resistant cancer cells. Such effects are likely driven by both tumor intrinsic and tumor extrinsic changes in response to therapy-induced stress. Identifying approaches to blunt these changes during exposure to chemotherapy could provide a therapeutic avenue to prevent the emergence of aggressive tumor cells following anti-cancer treatment. Sustained exposure to genotoxic stress can drive cells into a stable cell cycle exit known as cellular senescence. Exposure to chemotherapy represents a well-recognized pro-senescent stimulus. In addition to a stable cell cycle exit, senescent cells are characterized by their ability to secrete a discrete set of pro-inflammatory cytokines and chemokines, referred to as the SASP (Senescence Associated Secretory Phenotype). Importantly, we and others have demonstrated that the presence of SASP is sufficient to promote invasive and migratory phenotypes in breast cancer cells. Therefore, we propose that chemotherapy promotes the acquisition of aggressive traits in cancer cells at least in part through exposure to the SASP secreted by host and cancer cells rendered senescent as a result of the treatment. We will test the overarching hypothesis that targeting the chemotherapy-induced SASP or its downstream targets could serve as an adjuvant therapy to blunt the emergence of aggressive breast tumors after treatment. Specifically, we will: identify the cell population responsible for SASP production in vivo after exposure to chemotherapy, and assess the impact of inhibiting IL-1?, a master regulator of the SASP, on chemotherapy- induced emergence of aggressive breast cancer cells in mouse models (aim 1). We will also ascertain whether expression of lipocalin 2 (LCN2), a known pro-metastatic factor in breast cancer which we found strongly upregulated in breast cancer cells exposed to the SASP, correlates with exposure to chemotherapy in samples from human breast cancer patients. Furthermore, we will test whether LCN2 inhibition blunts the SASP-induced migratory and invasive phenotype in vitro, and mitigates the occurrence of metastases following chemotherapy treatment in vivo (aim 2). The long-term goal of this research is to identify novel therapeutic targets to prevent the resurgence of aggressive breast cancer.
Cellular senescence, a biological response to exposure to stress, including chemotherapy, is believed to prevent cancer progression. However, some phenotypes associated with cellular senescence, including invasion and metastasis, result in cancer progression. We propose to investigate how senescence promotes cancer progression, and to identify novel therapeutic means to prevent breast cancer progression following exposure to chemotherapy.
