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A Mechanistic Investigation of the Role of RhoA and RKIP in Breast Cancer Invasion and Metastasis

Kalpana, Gardiyawasam

Abstract Details

2019, Doctor of Philosophy (PhD), University of Toledo, Biomedical Sciences (Cancer Biology).
Tumor metastasis suppressors impede secondary tumor formation by inhibiting one or more steps of the metastasis cascade without stimulating primary tumor growth. Raf-1 kinase inhibitor protein (RKIP) is a metastasis suppressor that inhibits breast and prostate cancer metastasis. The molecular mechanism through which RKIP executes its anti-metastasis effects is not yet completely defined. The objective of the current study is to understand how RKIP inhibits breast cancer cell invasion and metastasis at the molecular level. Given their primary functions in actin cytoskeleton dynamics and cell movement regulation, Rho GTPases were studied as possible downstream effectors of RKIP. Among all Rho GTPases, RhoA has both pro-metastatic and anti-metastatic cell-context dependent functions. In this study, we demonstrate that the increased anti-metastatic activity of RhoA is one of the causes of RKIP-mediated suppression of breast cancer metastasis. Upon RNAi-mediated RhoA gene knockdown, more tumor cells were detected in the sentinel lymph node and more colonies in the lungs, suggesting that RhoA suppresses breast cancer lymph node and lung metastasis. Further characterizations showed that RhoA suppresses breast cancer lung metastasis partly due to upstream RKIP-dependent signaling and this is mediated through downstream E-cadherin and CCL5. Additionally, RhoA’s effect on tumor chemokine receptor expression and infiltration of SMA+ cells are independent of upstream RKIP signaling and might be mediated by RKIP-independent upstream RhoA regulators.
Kam Yeung (Committee Chair)
Kathryn Eisenmann (Committee Member)
Ivana de la Serna (Committee Member)
Saori Furuta (Committee Member)
Rafael Garcia Mata (Committee Member)

Recommended Citations

Citations

  • Kalpana, G. (2019). A Mechanistic Investigation of the Role of RhoA and RKIP in Breast Cancer Invasion and Metastasis [Doctoral dissertation, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=mco1564782498788212

    APA Style (7th edition)

  • Kalpana, Gardiyawasam. A Mechanistic Investigation of the Role of RhoA and RKIP in Breast Cancer Invasion and Metastasis. 2019. University of Toledo, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=mco1564782498788212.

    MLA Style (8th edition)

  • Kalpana, Gardiyawasam. "A Mechanistic Investigation of the Role of RhoA and RKIP in Breast Cancer Invasion and Metastasis." Doctoral dissertation, University of Toledo, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=mco1564782498788212

    Chicago Manual of Style (17th edition)