Grants and Contracts Details
Obesity is associated with a 35% to 40% increased risk of breast cancer recurrence and poor survival outcomes. One feature of obese adipose tissue is the excess extracellular matrix (ECM) deposition/remodeling in the form of fibrosis. However, function and regulation of obesity-related ECM deposition/remodeling in cancer progression largely remain to be determined. We recently identified Hsp47, a chaperone protein facilitating collagen secretion, as a hub of the ECM transcription network. Our new data showed that Hsp47 was highly expressed in adipose tissue. Importantly, increased Hsp47 expression in human and mouse adipose tissues was significantly associated with obesity development. We found that adipocyte-specific deletion of Hsp47 was sufficient to suppress high fat diet (HFD)-induced obese and mammary tumor growth, which is accompanied by reduced collagen deposition/alignment and macrophage infiltration in adipose tissue. The overall objective of this proposal is to define the mechanism by which adipocyte Hsp47 promotes obese-related fibrosis and breast cancer progression and to explore the value of Hsp47 as a potential target to suppress obesity- associated cancer progression. Using unbiased proteomics analysis, we identified asporin as a new target of Hsp47 in adipocytes. Based on these data, the central hypothesis of this proposal is that Hsp47 induces obesity-related fibrosis by facilitating asporin secretion in adipocytes, and subsequently enhances adipocyte plasticity and breast cancer progression. Following aims are proposed to test our hypothesis: Aim 1. Elucidate the molecular mechanism by which adipocyte Hsp47 induces obesity- and cancer-associated ECM remodeling; Aim 2. Determine how Hsp47 regulates obesity-associated and cancer-induced adipocyte plasticity; Aim 3. Define the potential of targeting Hsp47 to suppress obesity- associate fibrosis, inflammation, and breast cancer progression/metastasis.
|Effective start/end date||3/3/17 → 5/31/27|
- National Cancer Institute: $363,375.00
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