No abstract

Development of chemoresistance in breast cancer patients greatly increases mortality. Thus, understanding mechanisms underlying breast cancer resistance to chemotherapy is of paramount importance to overcome this clinical challenge. Although activated Notch receptors have been associated with chemoresistance in cancer, the specific Notch ligands and their molecular mechanisms leading to chemoresistance in breast cancer remain elusive. Using conditional knockout and reporter mouse models, we demonstrate that tumor cells expressing the Notch ligand Dll1 is important for tumor growth and metastasis and bear similarities to tumor-initiating cancer cells (TICs) in breast cancer. RNA-seq and ATAC-seq using reporter models and patient data demonstrated that NF-κB activation is downstream of Dll1 and is associated with a chemoresistant phenotype. Finally, pharmacological blocking of Dll1 or NF-κB pathway completely sensitizes Dll1+ tumors to chemotherapy, highlighting therapeutic avenues for chemotherapy resistant breast cancer patients in the near future.

Breast cancer is the second leading cause of cancer-related death in women and is a complex disease with high intratumoral and intertumoral heterogeneity. Such heterogeneity is a major driving force behind failure of current therapies and development of resistance. Due to the limitations of conventional therapies and inevitable emergence of acquired drug resistance (chemo and endocrine) as well as radio resistance, it is essential to design novel therapeutic strategies to improve the prognosis for breast cancer patients. Deregulated Notch signaling within the breast tumor and its tumor microenvironment (TME) is linked to poor clinical outcomes in treatment of resistant breast cancer. Notch receptors and ligands are also important for normal mammary development, suggesting the potential for conserved signaling pathways between normal mammary gland development and breast cancer. In this review, we focus on mechanisms by which Notch receptors and ligands contribute to normal mammary gland development and breast tumor progression. We also discuss how complex interactions between cancer cells and the TME may reduce treatment efficacy and ultimately lead to acquired drug or radio resistance. Potential combinatorial approaches aimed at disrupting Notchand TME-mediated resistance that may aid in achieving in an improved patient prognosis are also highlighted.Breast cancer is the most prevalent cancer among women worldwide (ShahidSales et al. 2018;Ghasemi et al. 2019). Breast cancer is a highly heterogeneous disease with many subtypes, and treatment choice is based on the presence or absence of different hormone receptors, such as estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), as well as tumor grade and age of the patient (Desmedt et al. 2008). Unfortunately, traditional treatment methods, including chemotherapy, endocrine therapy, and radiation therapy are often not curative, and only im-prove clinical outcome (Schmidberger et al. 2003;

Among the known Toll-like receptors (TLRs), Toll-like receptor 2 (TLR2) is a key sensor for detecting Staphylococcus aureus invasion. But the function of TLR2 during S. aureus infection in different cell populations is unclear. Two different cell subtypes were chosen to study the interaction of S. aureus with TLR2 because macrophages are extremely different from one compartment to another and their capacity to respond to live bacteria or bacterial products differs from one site to another. The contribution of TLR2 to the host innate response against acute live S. aureus infection and heat-killed S. aureus (HKSA) using anti-TLR2 antibody in murine peritoneal macrophages and resident fresh bone marrow cells has been investigated here. TLR2 blocking before infection induces the release of interleukin (IL)-10 by macrophages thereby inhibiting excessive production of oxidants by activating antioxidant enzymes. TLR2-blocked peritoneal macrophages showed impaired release of tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ) and IL-6 in response to both live and heat-killed S. aureus infection except bone marrow cells. TLR2-mediated free radical production and killing of S. aureus were modulated by TLR2 blocking in peritoneal macrophages and resident bone marrow cells. This study supported that S. aureus persists in resident bone marrow cells in a state of quiescence.

Resistance to radiotherapy is a major obstacle for effective cancer treatment. Both cancer-associated fibroblasts (CAF) within the tumor microenvironment (TME) and Notch signaling are implicated in radioresistance, but their potential interrelationship is unclear. Here, we report that irradiated samples obtained from luminal breast cancer patient tumors express higher levels of the Notch ligand Dll1 and have a greater number of αSMA- and FAP-expressing activated CAFs. Single cell transcriptomic profiles further revealed enrichment of an αSMA+ myofibroblastic subpopulation of CAF in Dll1+ tumors. In murine and human PDX models, Dll1+ tumor cells were more radioresistant than Dll1- tumor cells, and genetic and pharmacological blocking of Dll1-mediated Notch signaling decreased the number of Dll1+ cancer stem cells (CSC) and CAFs and increased Dll1+ tumor cell radiosensitivity. Dll1+ cells recruited CAFs in an IL-6-dependent fashion and promoted Wnt ligand secretion by Notch2/3-expressing CAFs, thereby driving Wnt/β-catenin-dependent increases in Dll1+ CSC function to promote metastasis. Treatment with the porcupine inhibitor LGK-974 that inhibits Wnt ligand secretion or pharmacological blockade of IL-6 or Dll1 suppressed CAF-dependent enhancement of Dll1+ CSC function and metastasis in radioresistant tumors. Together, these findings reveal an essential crosstalk between Dll1+ cancer cells and CAFs that promotes metastasis and radioresistance, which could be therapeutically exploited to improve the outcome of breast cancer patients.