Integrin-mediated Regulation of TGFbeta Signaling and Tumorigenesis

Case Western Reserve University, Cleveland OH

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Abstract

DESCRIPTION (provided by applicant): Breast cancer is a heterogeneous disease comprised of at least 5 major tumor subtypes that coalesce as the second leading cause of cancer death in women in the United States. Amongst individual breast cancer subtypes, those classified as being triple-negative breast cancers (TNBCs) are clinically unique via their presentation of aggressive and metastatic phenotypes, and their high propensity to recur rapidly following conventional chemotherapy treatment. TNBCs are also noteworthy by their failure to express hormone receptors (estrogen and progesterone) and ErbB2/HER2, a phenotype that renders targeted chemotherapies (e.g., hormonal or HER2-directed) ineffective and contributes to the poor prognosis of TNBC patients. Although our understanding of the molecular features and clinical manifestations of TNBCs has increased in recent years, science and medicine still lack sufficient knowledge of TNBC development and progression to permit the synthesis of novel pharmaceuticals capable of specifically targeting and alleviating this lethal breast cancer subtype. Transforming growth factor-ß (TGF-ß) is a powerful suppressor of mammary tumorigenesis. Interestingly, late-stage TNBCs respond to TGF-ß as if this cytokine were a tumor promoter, leading to the acquisition of metastatic and stem cell phenotypes. Although the molecular mechanisms underlying the conversion of TGF-ß function from that of a tumor suppressor to a tumor promoter in TNBCs remains incompletely understood, our laboratory recently defined a novel integrin-based signaling module that facilitates oncogenic TGF-ß signaling in TNBCs. Along these lines, we find the expression and activity of lysyl oxidase (LOX) to contribute to oncogenic TGF-ß signaling in part due to alterations in mechanotransduction. Based on these and other preliminary findings, we hypothesize that integrin switching underlies metastatic progression of TNBCs driven TGF-ß. A corollary states that developing novel chemotherapeutics to prevent integrin switching and oncogenic TGF-ß signaling will significantly improve the overall survival rates of TNBC patients. These hypotheses will be addressed by four Specific Aims. Aim 1 will determine the role of integrins and focal adhesion complexes during initiation of the TGF-ß Paradox by mechanotransduction. We will manipulate, both positively and negatively, the expression of B1 and B3 integrin and their effectors to gauge their function in coupling mechanotransduction to the oncogenic activities of TGF-ß both in vitro and in vivo. Likewise, the ability of mechanotransduction and Smad2/3 signaling to epigenetically silence E-cadherin expression during TNBC metastasis will be assessed. Aim 2 will determine the role of LOX family members in mediating oncogenic TGF-ß signaling in TNBCs. Additionally, genetic and pharmacological inactivation of LOX family members will be undertaken to assess their function in driving TNBC metastasis stimulated by TGF-ß. Aim 3 will map the transcriptome and epigenetic events coupled to TNBC development and metastatic progression. The presence of identified epigenetic marks in patient breast cells isolated by random periareolar fine needle aspiration will be determined to assess their utility as predictive TNBC biomarkers. Lastly, Aim 4 will visualize TGF-ß signaling during metastatic progression of TNBCs through the use of dual bioluminescent imaging. Simultaneous CTL1-based MRI approaches will be employed to monitor corresponding changes in tumor reactive stroma, as well as determine how conventional chemotherapies impact these metastatic events. Collectively, these studies will provide valuable information on how TGF-ß, integrins, and mechanotransduction cooperate in promoting the EMT, invasion, and metastasis of TNBCs, and more importantly, on how to control these deadly processes by inactivating the oncogenic activities of TGF-ß. Moreover, translating our epigenetic biomarkers to clinical diagnostic applications will enable science and medicine to significantly improve the overall survival of patients with TNBCs.