All ETDs from UAB

Advisory Committee Chair

Danny R Welch

Advisory Committee Members

Xu Feng

Andra R Frost

Richard D Lopez

Andrea M Mastro

Ralph D Sanderson

Document Type

Dissertation

Date of Award

2010

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Metastatic disease accounts for the overwhelming majority of cancer related deaths. More specifically, breast cancer remains one of the leading causes of death in women and breast cancer cells metastasize to bone more than any other secondary site. Upon arriving within the bone microenvironment, breast cancer cells interact with bone marrow cells, leading to changes in bone biology that favor growth of the cancer cells. Additionally, some cancer cells are capable of direct cellular communication with cells at metastatic sites via dysregulation of a family of proteins known as connexins. This direct, physical communication is known as gap junctional intercellular communication (GJIC) and can aid in the initial survival and proliferation of metastatic cells. The understanding of how breast cancer cells interact at secondary sites, specifically bone, will lead to more efficacious therapies for patients with metastasis. In the first portion of this thesis, I set out to examine the molecular mechanisms responsible for GJIC (dys)regulation in tumorigenic and metastatic cell lines. I demonstrate the delineation of two common signaling pathways in relation to GJIC in cancer cells, PI3K and PKA , and show that PKA mediated regulation of connexin proteins is often altered during tumorigenesis and its restoration is capable of causing connexin subcellular relocalization and a corresponding increase in GJIC. I also examine a possible role for the metastasis suppressor BRMS1 in mediating changes in GJIC through modulation of potassium channels. In the second portion, I studied the interactions of breast cancer cells with osteoblasts both in vitro and in vivo using a murine xenograft model of breast cancer induced osteolysis. The results provided novel data that osteoblasts play roles in promoting breast cancer cell proliferation in early stages of bone metastasis, highlighting an underappreciated interaction between these cell types. Collectively, the data presented here provide important discoveries on two aspects of breast cancer cell bone metastasis: breast cancer cell dysregulation of connexin function, and communication with osteoblasts.

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