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An investigation of Atf3, an adaptive-response gene, in breast cancer chemotherapy and stress response.

Jalgaonkar, Swati
http://orcid.org/0000-0003-3895-3723
http://rave.ohiolink.edu/etdc/view?acc_num=osu1460387137

Abstract Details

2016, Doctor of Philosophy, Ohio State University, Molecular, Cellular and Developmental Biology.
Activating Transcription factor 3 (Atf3) is induced by perturbations in the cellular environment (stress). Overwhelming evidence in literature links ATF3 with diverse human diseases associated with inflammation, including cancer. Here, I explore two distinct and novel aspects of ATF3 function: (1) the role of ATF3 in the host—the organism carrying cancer—in the context of breast cancer chemotherapy. We previously reported that ATF3 expression in the host promotes breast cancer metastases in several mouse models and the data are clinically relevant. Given the importance of host-ATF3 in breast cancer progression, and because ATF3 is induced by numerous chemotherapeutic drugs, in this study we further asked if host-ATF3 modulates chemotherapy efficacy in breast cancer. This is an important issue because clinically about one-third of the breast cancer patients display chemoresistance and disease relapse; an emerging concept in the field suggests that host-derived factors contribute to this. To investigate the role of host-ATF3 in the context of breast cancer chemotherapy, we injected the same cancer cells into the fat pad of wild type (WT) mice and Atf3-null mice (ATF3 KO), and treated them with paclitaxel (PTX)—a common clinical drug—or saline (control). Strikingly, we found that in WT mice PTX treatment aggravated breast cancer metastases at a dose that was therapeutic for the primary tumor. By contrast, PTX did not enhance breast cancer metastases in the KO mice. I focused on the analyses of primary tumors to elucidate how the host-ATF3 and PTX may affect cancer cell escape from the tumors. My analysis reveals that host-ATF3 regulates key features within the primary tumor that may contribute to cancer cell escape—an early step in metastases: (i) decreased pericyte coverage on tumor vasculature (indicative of leaky vasculature), (ii) an increased ability of a sub-set of macrophages to induce cancer cell invasion, and (iii) higher “tumor microenvironment for metastases” (TMEM)—sites for cancer cell escape from primary tumor—in the PTX-treated WT mice. Importantly, the functional consequence is the increased circulating tumor cells in PTX-treated WT mice. Taken together, the data identifies potential ways in which host-ATF3 promotes an overall environment conducive for cancer cell dissemination from the primary tumor. (2) Development of a novel mouse model to trace stressed cells in vivo. So far there are no animal models that can be used to trace stressed cells in vivo. Since Atf3 transcription is rapidly and transiently induced in numerous cell types by varied stressors, we propose that we can use Atf3 as a “handle” to study cellular fates in diverse stress paradigms. Briefly, the proposed transgenic mice would contain two alleles: (i) an inducible Cre driven by the entire Atf3 genomic locus (the Atf3-Cre* allele) and (ii) a ROSA26 reporter allele. The rationale is that the Atf3-Cre* mice will express Cre* only in stressed cells. Here, I generated and characterized a transgenic mouse line, Atf3-Cre*, that can be crossed with commercially available ROSA reporter mice (ROSA26-lox-STOP-lox-reporter) to generate the final double transgenic mice for tracing purposes. Taken together, work presented in this dissertation identifies ATF3 as a key molecule that coordinates host responses to breast cancer chemotherapy and also provides a proof-of-concept for using Atf3 gene as a tool to study cellular stress response in vivo.
Tsonwin Hai (Advisor)
Sujit Basu (Committee Member)
James Jontes (Committee Member)
Mariano Viapiano (Committee Member)
216 p.
Cellular Biology; Developmental Biology; Molecular Biology; Oncology
Activating Transcription Factor 3; Host; tumor microenvironment; breast cancer metastases; paclitaxel chemotherapy; stress gene; in vivo cell fate tracing

Recommended Citations

Citations

  • Jalgaonkar, S. (2016). An investigation of Atf3, an adaptive-response gene, in breast cancer chemotherapy and stress response. [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1460387137

    APA Style (7th edition)

  • Jalgaonkar, Swati. An investigation of Atf3, an adaptive-response gene, in breast cancer chemotherapy and stress response. 2016. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1460387137.

    MLA Style (8th edition)

  • Jalgaonkar, Swati. "An investigation of Atf3, an adaptive-response gene, in breast cancer chemotherapy and stress response." Doctoral dissertation, Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1460387137

    Chicago Manual of Style (17th edition)

osu1460387137
149
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This open access ETD is published by The Ohio State University and OhioLINK.