Basal-like breast cancer (BLBC) consistently expresses genes typical of normal basal/myoepithelial cells of the breast and comprises up to 25% of all breast cancer. It is associated with aggressive clinical behavior and a high rate of metastasis to the lung. The organ-preferential metastasis of BLBC is poorly understood. Of note, the vast majority of breast tumors arising in BRCA1 mutation carriers display a basal-like phenotype. Little is currently known about the molecular basis of the tissue and subtype-specific features of BRCA1-mutant breast cancer. We found that the transcription factor FOXC1 is exclusively induced in BLBC including BRCA1-mutant breast cancer and correlates with poor clinical outcome. It regulates breast cancer cell function by inducing NF- ?B and other cancer-associated signaling pathways. Its overexpression in the mouse mammary gland increases the luminal progenitor population, which is postulated to be the cell of origin of BRCA1-mutant breast cancer. We also found that FOXC1 and its targets CXCL1, 2, and 8 chemokines are essential for BLBC lung metastasis. These chemokines act in concert with lung fibroblasts to induce endothelial cell migration in vitro. We therefore hypothesize that FOXC1 counteracts the detrimental effects of BRCA1 mutations in breast cells and plays a critical role in basal-like BRCA1-mutant breast cancer development. In addition, we hypothesize that the chemokines CXCL1, 2, and 8 mediate the effect of FOXC1 on BLBC lung metastasis by engaging lung fibroblasts to induce angiogenesis.
In Aim 1, we will determine the role of FOXC1 in the development of BRCA1-mutant breast cancer with the basal-like phenotype. BRCA1-mutant breast cancer cell models will be used to test whether FOXC1 signaling pathways regulate cell function and counteracts the increase of reactive oxygen species in breast epithelial cells with BRCA1 mutations or deficiency. We will determine whether FOXC1 regulates mammary tumorigenesis in BRCA1-mutant xenograft models and a mammary-specific BRCA1-deficient mouse model.
In Aim 2, we will define a FOXC1/chemokine-mediated mechanism for BLBC lung metastasis. Tail vein injection mouse models will be used to investigate whether the FOXC1-induced chemokines promote the proliferation and survival of metastatic breast cancer cells in the lung tissue microenvironment. We will determine whether FOXC1 overexpression in BLBC leads to increased angiogenesis in lung metastases mediated by chemokine-directed crosstalk between metastatic breast cancer cells and lung fibroblasts. We will further investigate the mechanism whereby FOXC1 regulates the three chemokines in BLBC cells. Basal-like BRCA1-mutant breast cancer development and BLBC metastasis are poorly understood areas that are of paramount importance in breast cancer. Our results will shed light on their biological basis and will lay down a foundation for new approaches that can prevent and treat FOXC1- overexpressing breast cancer.
FOXC1 is a protein highly expressed in basal-like breast cancer, an aggressive type of breast cancer. We will determine whether FOXC1 plays a role in mutant BRCA1 protein-induced basal-like breast cancer development and whether it activates chemokine gene expression to regulate basal-like breast cancer lung metastasis. Our study may shed light on a FOXC1-mediated mechanism of basal-like breast cancer development and metastasis and may establish it as a potential therapeutic target for breast cancer treatment. 1
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