It is widely presumed that the increased risk of developing breast cancer following pregnancy is due to the ability estrogen to promote the further proliferation of an initiated target cell population. However, since the majority of breast cancers that do develop during this time lack appreciable expression of either the estrogen (ER)or progesterone receptors (PR), this suggests that if hormonal changes play a part in promoting breast cancer, they may not be doing so through direct binding to hormone receptor molecules expressed by breast epithelial cells. Moreover, it is well established that ovariectomy prevents the formation of both ER-positive as well as ER-negative breast cancers in women, further highlighting the importance of estrogens in the development of ER-negative cancers. To reconcile this conceptual conflict we investigated the hypothesis that estrogen promotes the outgrowth of ER-negative cancers by influencing host cell types distinct from the breast epithelium itself. We utilized a novel xenograft mouse model in which the tumors that arise lack the expression of nuclear hormone receptors, recapitulating the clinical situation described above. Despite lacking ER expression,we showed that the tumors that develop in this model require circulating estrogens for their formation. Moreover, we demonstrated that increasing the levels of circulating estrogens is sufficient to promote the formation and progression of ER-negative cancers via a systemic increase in angiogenesis. Remarkably, the systemic enhancement of neo-angiogenesis was accompanied by a striking increase in the recruitment of bone marrow derived cells into the growing tumor mass, including endothelial and stromal cells. Based on our evidence, we now propose to determine the mechanism by which estrogen effects bone marrow cell recruitment, angiogenesis and tumor promotion. To this end, we aim to determine whether ER expression by the host is necessary for the stromal effects mediated by estrogens, and whether these actions occur through the genomic or non-genomic actions of ER signaling. In addition, we also aim to determine if bone marrow mesenchymal stem cells are the targets of estrogen-mediated angiogenesis and tumor promotion. This will be investigated through the use of ERKO mouse models, bone marrow cell fractionation, and in vivo and in vitro functional assays to estrogen signaling. Most recently, superior and more specific endocrine therapies targeting estrogen synthesis, turnover, as well as genomic and non-genomic activities of the receptor have been developed, however they are only utilized for the treatment of ER-positive breast cancers due to the lack of evidence these compounds would work in ER-negative tumors. Thus, understanding the mechanism by which estrogen can promote bone marrow cell recruitment, angiogenesis, and tumor growth would have significant and highly relevant scientific and clinical impact for ER-negative cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA125554-02
Application #
7332220
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Mohla, Suresh
Project Start
2006-12-15
Project End
2011-11-30
Budget Start
2007-12-01
Budget End
2008-11-30
Support Year
2
Fiscal Year
2008
Total Cost
$310,650
Indirect Cost
Name
Tufts University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
039318308
City
Boston
State
MA
Country
United States
Zip Code
02111
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Xu, Kun; Tian, Xuejun; Oh, Sun Y et al. (2016) The fibroblast Tiam1-osteopontin pathway modulates breast cancer invasion and metastasis. Breast Cancer Res 18:14
Sedic, Maja; Kuperwasser, Charlotte (2016) BRCA1-hapoinsufficiency: Unraveling the molecular and cellular basis for tissue-specific cancer. Cell Cycle 15:621-7
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Arendt, Lisa M; Keller, Patricia J; Skibinski, Adam et al. (2014) Anatomical localization of progenitor cells in human breast tissue reveals enrichment of uncommitted cells within immature lobules. Breast Cancer Res 16:453
McCready, Jessica; Arendt, Lisa M; Glover, Eugene et al. (2014) Pregnancy-associated breast cancers are driven by differences in adipose stromal cells present during lactation. Breast Cancer Res 16:R2

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