Obesity has been identified as an important risk factor for postmenopausal breast cancer and is significantly correlated with diminished treatment response. It is currently not understood how inflammation within obese breast fat contributes to adipose tissue fibrosis and tumor desmoplasia. These conditions have been associated with both increased breast cancer risk and chemotherapy resistance. The long-term goal is to understand how obesity increases local and systemic inflammation leading to progression of treatment-resistant breast tumors. Preliminary studies have shown that transplant of CCL2+ breast stromal cells with transformed breast epithelial cells promoted rapid breast cancer development, with increased numbers of cancer stem-like cells (CSCs). Transient depletion of CD11b+ cells early in tumor development resulted in dramatic reductions in cancer associated fibroblasts (CAFs) and tumor growth rates. Transcriptional analysis of CD11b+ cells from both tumors and mammary glands of obese mice revealed a fibrotic gene signature and expression of platelet-derived growth factor receptor alpha (PDGFR?). This fibrotic gene signature is consistent with fibrocytes, which have attributes of both inflammatory macrophages and myofibroblasts. Based on these preliminary data, the central hypothesis is that fibrocytes are increased by obesity where they promote aggressive tumor growth and chemotherapy resistance through the expansion of CSCs via PDGFR?. This hypothesis will be tested with three specific aims: 1) Examine how fibrocytes are recruited to obese mammary fat and promote fibrosis via PDGFR?; 2) Determine how fibrocytes differentiate into CAFs and promote chemotherapeutic resistance through cancer stem-like cell (CSC) expansion; 3) Identify how obesity enhances fibrocytes in human breast tissue leading to adipose tissue fibrosis and desmoplasic, treatment-resistant breast tumors. A high fat diet model of obesity and GFP-labeled myeloid lineage cells will be used to examine differentiation of obesity-induced fibrocyte populations within the mammary gland. Gleevec, a clinical PDGFR inhibitor, will be used to target fibrocytes and reduce obesity- induced fibrosis. Using the inflammatory model of breast tumor progression, the mechanism of fibrocyte-induced tumor desmoplasia and CSCs expansion will be examined. The efficacy of Gleevec will be tested to reduce CSCs and enhance chemotherapy response. Reduction mammoplasty tissue from obese and lean women and well-annotated breast tumor tissue microarrays will be used to understand how obesity alters treatment response and tumor desmoplasia, and potentially identify patients that might benefit from adjuvant use of Gleevec for treatment of breast cancer. These studies are innovative because fibrocytes have not been investigated in the context of obesity. The impact of these studies is that targeted Gleevec therapy to treat desmoplastic tumors in obese women may significantly improve chemotherapeutic response, leading to reduced mortality. Obesity has been linked to tumor desmoplasia and treatment resistance in other cancers, and understanding the role of fibrocytes in therapy resistance may lead to broad-reaching advances for other obesity-associated cancers.
The proposed research is relevant to public health because obesity has become an epidemic in the US, and there is a critical need to develop identify new therapeutic targets for aggressive breast tumors in obese women to prevent treatment resistance, recurrence and metastasis. These studies contribute to the mission of the Provocative Questions Initiative to address the understudied problem of how variations in immune function caused by the comorbidity of obesity affect response to cancer therapy.
