Breast cancer is the leading cancer diagnosis in pre-menopausal women in the U.S. Of these breast cancers, 25% are diagnosed 2-5 years post-partum. Unfortunately, post-partum breast cancers (ppBCs) are highly metastatic. The reasons underlying the exaggerated lethality of ppBCs are unclear, but relate to stromal remodeling events that occur during post-partum involution, when milk-producing mammary epithelial cells (MECs) undergo widespread cell death. Upon engulfment of apoptotic cells (efferocytosis), immune suppressive wound healing cytokines are produced including Tgfβ1, IL4, and IL10, which increase macrophage polarization towards an M2 phenotype. Wound healing/TH2-like cytokines and M2 macrophages each correlate with decreased disease-free survival in breast cancer patients. Transforming growth factor (TGF)-β1 is a pleiotropic cytokine that has gained interest for its role in both tumor progression and metastasis. TGFβ1 operates to suppress cytotoxic immunity, increase fibroblast activation and collagen deposition, increases migration and invasion of tumor epithelial cells, and may enhance cancer stem cell-like properties in some tumor cells. TGFβ1 is abundantly up-regulated in response to efferocytosis during post-partum involution of the mammary gland. We recently showed that TGFβ1 is induced upon macrophage-mediated efferocytosis in the mammary tumor microenvironment (TME). Secreted TGFβ1 also acts on mammary tumor epithelial cells to increase epithelial-mesenchymal transition (EMT), cell adhesion, motility, and invasion. We utilized an immune-competent mouse model of ppBC, which recapitulates many of the clinical aspects of ppBCs in patients, including increased metastasis in response to post-partum events to show that inhibition of efferocytosis for the first 7 days of involution prevents M2 macrophage polarization, blocks induction of TGFβ1, and prevents metastasis of ppBCs through involution day 40. Our preliminary results show that ppBCs treated with the neutralizing anti-TGFβ antibody 1D11 for the first 14 d of involution produce fewer lung metastases as compared to control IgG-treated ppBCs.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-12022014-140155 |
| Date | 02 December 2014 |
| Creators | Williams, Andrew John |
| Contributors | Rebecca S. Cook, Ph.D., Jin Chen, M.D., Ph.D. |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-12022014-140155/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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