BS3-1: Extrinsic and Intrinsic Force Regulation of Breast Cancer Progression and Treatment.

Breast tissue development and homeostasis are tightly regulated by mechanical cues. Alterations in tensional homeostasis characterize breast cancer. The challenge is to clarify how chemical and mechanical cue collaborate to regulate breast tissue function and to determine when and how these forces regulate breast cancer behavior. The Weaver group has been studying how cells in the breast sense and transduce mechanical cues to regulate their behavior and how altered mechanical force compromises breast tissue homeostasis to drive cancer (Dufort et al., Nature Mol Biol Rev 2011). Our work focuses on clarifying the role of force in normal breast behavior and in breast cancer initiation, transformation, metastasis and treatment response. We showed that extracellular matrix (ECM) stiffness, which is tightly controlled through matrix concentration, topology and posttranslational modifications, is a critical isometric force that modulates mammary gland morphogenesis and tumorigenesis. We demonstrated that the ECM associated with the mammary epithelium progressively stiffens as the tissue transforms and that breast cancer subtype is characterized by increasing ECM stiffness. Thus, normal human breast tissue is quite soft, the ECM associated with fibrocystic lesions is twice as stiff, ER/PR+ve invasive breast cancers are 4 fold stiffer and triple negative breast lesions are the stiffest (6-10 times stiffer). We showed that a stiffened ECM modifies breast tissue behavior by promoting the assembly of integrin focal adhesions which potentiate growth factor receptor signaling and induce cytoskeletal remodeling and actomyosin contractility (Paszek et al., Cancer Cell 2005; Paszek et al., PLOS Computational 2009). We determined that ECM stiffness also potentiates the tumor promoting effect of oncogenes such as Ras, EGFR and ErbB2 by increasing the activity of ERK, wnt and PI3 kinase and inducing tissue fibrosis. Inducing ECM stiffness promotes the malignant transformation of pre malignant oncogenically-primed mammary epithelial cells, whereas inhibiting ECM stiffening prevents breast tissue fibrosis and tumor progression and metastasis (Levental et al., CELL 2009). Importantly, the tissues response to force also depends upon the cellular mechanoresponsive machinery and we determined that oncogenic transformation and elevated chemokine and cytokine signaling induces aberrant force sensing and elevated breast tumor tension. Most notably we demonstrated that oncogenic signaling through Ras signaling to ERK induces ECM remodeling and stiffening which are required to stimulate wnt thereby driving tumor cell invasion to induce an epithelial to mesenchymal like transition that potentiates breast tumor aggression and metastasis. More recently we found that ECM stiffness dictates the efficacy of treatment response - with high ECM stiffness potentiating chemo, immune and radiation-induced tumor regression and apoptosis. The clinical relevance of these findings are now being investigated with collaborators at UCSF and Duke. (supported by DOD BCRP W81XWH-05-1-0330 and NCI U54CA143836-01, R01 CA138818-01A1, U01 CA151925-01, RO1 CA085492, and R01 CA140663-01A2 to VMW, NIH grant 1U01ES009458-01 to ZW and NCI SPORE P50 CA058207 to VMW, CP, & SH). Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr BS3-1.