Breast cancer patients have an anomalously high rate of relapse or recurrence from dormancy after surgery or immunotherapy. There is a major lack of understanding of what regulates dormancy, and basic and translational research is badly needed in this area. Thus, characterization of novel cell types and the underlying signaling molecules in tumor recurrence will likely reveal optimal therapeutic targets to prevent/treat breast cancer recurrence from dormancy. At a cellular level, we propose that a specific type of bone marrow-originated cells known as fibrocytes inhibit breast cancer dormancy. This proposal is supported by published data showing that: 1). fibrocytes promote metastatic tumor growth in a mouse model of melanoma. 2). fibrocytes contribute to tumor progression via immune evasion. 3). fibrocytes possess the ability to generate fibroblasts, a major type of stromal cells supporting growth of high grade breast cancer. At a molecular level, we propose that a nuclear protein named Kruppel like factor 4 (KLF4) is critical to the generation of fibrocytes in regulating breast cancer dormancy because: 1). KLF4 deficiency drastically decreased the tumor growth in the metastatic lung in mouse models of breast cancer metastasis. This was accompanied by decreased numbers of fibrocytes. 2). KLF4 expression levels were tightly associated with the efficiencies of fibrocyte generation and expression levels of a protein named fibroblast-specific protein 1 (FSP1). Highly expressed FSP1 has been linked to recurrent mammary tumors. We thus hypothesize that fibrocytes promote breast cancer recurrence from dormancy in a KLF4/FSP1 axis-dependent manner. We designed the following three specific aims to test our hypothesis.
In Aim 1, we will isolate KLF4-deficient fibrocyte precursor cells from KLF4-deficient mice.
In Aim 2, we will perform a cause-effect study testing whether KLF4 deficiency in fibrocyte precursor cells leads to reduced tumor recurrence in two mouse models of breast cancer.
In Aim 3, we will establish a mechanistic link between the KLF4/FSP1 signaling and breast cancer recurrence. We anticipate that our studies will reveal a novel function of KLF4-controlled fibrocytes in breast cancer recurrence from dormancy. Successful completion of the project will be very helpful to determine whether KLF4 or its downstream molecules is a novel therapeutic target to extend tumor dormancy or eradicate dormant tumor cells in breast cancer patients.
Breast cancer recurrence from dormancy, the development of tumor growth in local or distant target organ sites after surgery or immunotherapy, leads to the greatest part of cancer-related mortality and morbidity. We propose to test the hypothesis that the expression of a nuclear protein named KLF4 in the bone marrow controls the recurrence of dormant tumor cells by regulating the differentiation of a subset of bone marrow cells. The data being developed from these studies will help to develop novel therapeutic strategies to treat and prevent breast cancer recurrence from dormancy by targeting KLF4.
