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Mechanisms of Chemoresistance in Breast Cancer and Liposarcoma

LaPensee, Elizabeth W.

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2008, PhD, University of Cincinnati, Medicine : Cell and Molecular Biology.

Chemotherapy is mainstay treatment for cancer patients, but unfortunately many tumors are resistant to therapy. Much research now focuses on identifying mechanisms that contribute to chemoresistance. The importance of such research lies in the fact that no other treatment has proven as effective in controlling cancer metastasis and preventing tumor recurrence. This thesis focuses on: 1) identifying a cellular model appropriate for studying chemoresistance in liposarcoma and 2) understanding the role of endogenous hormones, such as prolactin (PRL) and estradiol (E2), as well as the endocrine disruptor bishpenol A (BPA), in affecting anti-cancer drug efficacy in breast cancer cells.

Project 1: Our first goal was to compare the responsiveness of our LS14 liposarcoma cell line and SW872 liposarcoma cells to anti-cancer drugs and explore the mechanism(s) underlying chemoresistance. Using complementary assays for cell viability and apoptosis, we found that LS14 cells are much less respsonsive to anti-cancer drugs and have higher expression of the anti-apoptotic proteins Bcl-2 and Bcl-xL. In addition, LS14 cells are also tumorigenic in nude mice.

Project 2: The role of PRL as a survival hormone led to the hypothesis that PRL protects breast cancer cells from chemotherapy. We found that low dose PRL antagonized the cytotoxic effects of various anti-cancer drugs and prevented cisplatin-induced cell cycle arrest and apoptosis. γ-H2AX staining and mass spectroscopy reveal less DNA damage and less cisplatin bound to DNA in the presence of PRL. Glutathione s-transferase, which sequesters cisplatin in the cytoplasm, was dramatically increased by PRL; an effect abrogated by Jak and MAPK inhibitors. PRL did not antagonize cisplatin or prevent its binding to DNA in the presence of a GST inhibitor.

Project 3: Our third study focused on the roles of BPA and E2 in chemoresistance in breast cancer cells. BPA and E2 confer resistance to various anti-cancer drugs in both ERα-positive and -negative cells. Antagonists for ERα and ERβ revealed that BPA and E2 unlikely mediate their effects via either of these receptors. Both cell lines express non-classical estrogen receptors, including GPR30 and members of the ERR family. The ability of BPA and estradiol to alter the expression of Bcl-2 and/or increase proliferation are likely mechanisms by which they confer chemoresistance.

Overall Conclusions: The reduced responsiveness of LS14 cells to anti-cancer drugs more accurately reflects chemoresistance in patients. This, combined with their tumorigenicity, make LS14 cells an excellent model for exploring anti-cancer drug efficacy and resistance in liposarcoma.

Ours is the first study showing PRL antagonizes cisplatin by preventing its entry to the nucleus. Future therapies that reduce PRL levels or block its actions should be beneficial to breast cancer patients undergoing chemotherapy and allow for expanded drug options.

Ours is the first demonstration that BPA alters responsiveness to chemotherapy. Therapeutically, the measurement of BPA and E2 levels in breast cancer patients should allow for dosage adjustment and drug selection on a patient by patient basis.

Nira Ben-Jonathan, PhD (Committee Chair)
Arthur Buckley, PhD (Committee Member)
Kathleen Goss, PhD (Committee Member)
Nelson Horseman, PhD (Committee Member)
Peter Stambrook, PhD (Committee Member)
219 p.

Recommended Citations

Citations

  • LaPensee, E. W. (2008). Mechanisms of Chemoresistance in Breast Cancer and Liposarcoma [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1224593025

    APA Style (7th edition)

  • LaPensee, Elizabeth. Mechanisms of Chemoresistance in Breast Cancer and Liposarcoma. 2008. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1224593025.

    MLA Style (8th edition)

  • LaPensee, Elizabeth. "Mechanisms of Chemoresistance in Breast Cancer and Liposarcoma." Doctoral dissertation, University of Cincinnati, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1224593025

    Chicago Manual of Style (17th edition)