Obesity represents a key risk and prognostic factor for breast cancer, which most commonly presents as hormone receptor positive (HR+) disease in postmenopausal women. However, the molecular mechanisms underlying obesity-driven breast cancer remain poorly understood, which is particularly alarming given the obesity epidemic in the U.S. Hypoxia, altered extracellular matrix (ECM) deposition, and elevated stromal estrogen are characteristic of the obese microenvironment, but whether or not the integrated effects of these parameters functionally corroborate towards obesity-dependent breast tumorigenesis remains unclear. In obese adipose tissue, hypoxia is caused by diffusion-limited oxygen transport, which induces oxidative stress that can enhance fibrotic tissue remodeling via increasing myofibroblast differentiation. Myofibroblasts, in turn, elevate ECM stiffness, which not only perturbs epithelial morphogenesis, but can also impact macrophage recruitment and activation. Indeed, macrophage activation is elevated in obese vs. lean adipose tissue and enhance breast cancer risk by stimulating aromatase expression, an enzyme that catalyzes the conversion of androgen precursors to estrogens. Nevertheless, it remains unknown whether obesity-induced hypoxia promotes tumorigenesis via stiffness-dependent macrophage activation, and ultimately, enhanced estrogen synthesis. This project will investigate the overall hypothesis that hypoxia increases interstitial ECM stiffness in obese adipose tissue by elevating myofibroblast differentiation and that the resulting changes in ECM physicochemical properties promote malignancy (i) via direct effects on tumor cells and (ii) by altering macrophage-dependent induction of stromal aromatase expression and activity. To address this hypothesis, three specific aims will be pursued.
Aim 1 : Determine the ability of obesity-associated hypoxia to enhance interstitial ECM stiffness of mammary adipose tissue.
Aim 2 : Characterize the effects of increased ECM stiffness on HR+ mammary tumor cells and determine the ability of macrophages to enhance stromal aromatase.
Aim 3 : Assess the integrated effects of increased ECM stiffness and elevated stromal estrogen on HR+ tumorigenesis, and evaluate whether therapeutic reduction of stiffness can inhibit this process. These studies will be conducted using a multidisciplinary approach that leverages the engineering, biology, and clinical expertise of the investigative team. Collectively, the findings should establish a functional link between obesity and stiffness-dependent tumorigenesis of HR+ breast cancer, and motivate novel therapeutic strategies that interfere with these pathways. Insights gained by this project should also offer broad relevance to other non-breast cancers whose prevalence is similarly enhanced with obesity.

Public Health Relevance

Obesity represents an important risk and prognostic factor for breast cancer including its most common presentation hormone receptor positive disease in postmenopausal women; however, the underlying mechanisms remain unclear. This research will investigate the hypothesis that obesity induces tumor-like stiffening of interstitial breast tissue and that these changes promote breast tumorigenesis via direct effects on tumor cells and by altering macrophage functions ultimately enhancing local estrogen concentrations. The proposed studies will combine materials science with engineering and cancer biology, and this interdisciplinary approach has the potential to transform our understanding of obesity-associated breast cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA185293-02
Application #
8853835
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Snyderwine, Elizabeth G
Project Start
2014-06-01
Project End
2018-05-31
Budget Start
2015-06-01
Budget End
2016-05-31
Support Year
2
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Cornell University
Department
Engineering (All Types)
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
872612445
City
Ithaca
State
NY
Country
United States
Zip Code
14850
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Lourenço, Bianca N; Springer, Nora L; Ferreira, Daniel et al. (2018) CD44v6 increases gastric cancer malignant phenotype by modulating adipose stromal cell-mediated ECM remodeling. Integr Biol (Camb) 10:145-158
Druso, Joseph E; Fischbach, Claudia (2018) Biophysical Properties of Extracellular Matrix: Linking Obesity and Cancer. Trends Cancer 4:271-273
Song, Young Hye; Warncke, Christine; Choi, Sung Jin et al. (2017) Breast cancer-derived extracellular vesicles stimulate myofibroblast differentiation and pro-angiogenic behavior of adipose stem cells. Matrix Biol 60-61:190-205
Wang, Karin; Wu, Fei; Seo, Bo Ri et al. (2017) Breast cancer cells alter the dynamics of stromal fibronectin-collagen interactions. Matrix Biol 60-61:86-95
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Brown, Kristy A; Iyengar, Neil M; Zhou, Xi Kathy et al. (2017) Menopause Is a Determinant of Breast Aromatase Expression and Its Associations With BMI, Inflammation, and Systemic Markers. J Clin Endocrinol Metab 102:1692-1701
Springer, Nora L; Fischbach, Claudia (2016) Biomaterials approaches to modeling macrophage-extracellular matrix interactions in the tumor microenvironment. Curr Opin Biotechnol 40:16-23
Song, Young Hye; Shon, Seung Hee; Shan, Mengrou et al. (2016) Adipose-derived stem cells increase angiogenesis through matrix metalloproteinase-dependent collagen remodeling. Integr Biol (Camb) 8:205-15
Wang, Karin; Seo, Bo Ri; Fischbach, Claudia et al. (2016) Fibronectin Mechanobiology Regulates Tumorigenesis. Cell Mol Bioeng 9:1-11

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