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    Research Grants Awarded

    The tumor stroma as a regulator of resistance to endocrine therapy.

    Study Section:
    Tumor Cell Biology II

    Scientific Abstract:
    Tamoxifen (TAM), a selective estrogen receptor (ER) modulator, is the standard treatment for hormone receptor positive breast cancer. However, about one third of patients with ER- a positive tumors are refractory to TAM. Thus, understanding the mechanisms that lead to resistance is of great clinical importance. Activation of growth factor signaling pathways is implicated as a mechanism responsible for the development of hormone-resistance; however, to date there are no studies analyzing the role of the tumor microenvironment as a mediator of these effects, possibly due to the lack of experimental models where the stromal compartment of the tumor is available. Using a mouse model of estrogen responsive breast cancer, we found that tumor stromal cells were able to confer resistance to ER- a positive TAM sensitive epithelial cells. Thus we hypothesize that stromally derived microenvironmental epigenetic effectors could be responsible for modulating responsivess to endocrine therapy, and as such responsiveness could be reversible. The aims of this proposal are: 1) to determine the nature of the stromal factors responsible for the induction of hormone-resistance in the epithelial cells; 2) to find out whether alterations in cell-matrix interactions modulate resistance, and 3) establish whether resistance in vivo is reversible and thus due to epigenetic changes induced by the microenvironment, or irreversible due to permanent alterations in the cancer cell itself. Study design: we will carry out these experiments using the estrogen dependent M05 in vivo mouse mammary tumor, and the stable cell lines derived from it, LM05-Mix (composed of both epithelial and fibroblastic cells) and the stable LM05-E (epithelial) and LM05-F (fibroblastic) clones. Aims 1 and 2 will be carried out using the stable cell lines and aim 3 will be achieved using in vivo passages of the M05 tumor that are sensitive and resistant to endocrine therapy. Potential outcomes and benefits: to date experimental work on hormone refractory breast cancer has been focused on the epithelium of the tumor. Our preliminary data suggest that the stroma may be key in determining whether or not a tumor is resistant to TAM. Our results will contribute to a better understanding of the biology of TAM resistant breast cancer and may impact the rational for the development of therapies which may consider modulating the tumor microenvironment to overcome resistance to endocrine therapy.

    Lay Abstract:
    Tamoxifen (TAM) is the standard treatment for hormone receptor positive breast cancer; yet, about one third of patients do not respond to this treatment. Thus, understanding the mechanisms that lead to resistance is of great clinical importance. Breast tumors are composed of malignant epithelial cells which are surrounded by stromal cells and the extracellular matrix (ECM) that together define the tumor microenvironment. Although signaling pathways that are activated by stromal growth factors or ECM components have been implicated in the development of hormone-resistance; to date there are no studies analyzing the role of the tumor microenvironment as a mediator of these effects, possibly due to lack of adequate experimental models. Using a mouse model of estrogen responsive breast cancer, we found that stromal cells were able to modulate the sensitivity of epithelial tumor cells to TAM, making them resistant. Thus we hypothesize that stromally derived microenvironmental factors could be responsible for modulating responsivess to endocrine therapy, and as such responsiveness could be reversible. The aims of this proposal are: 1) to determine the nature of the stromal factors responsible for the induction of resistance; 2) to find out whether alterations in cell-matrix interactions modulate hormone resistance, and 3) establish whether resistance in vivo is reversible and thus due to changes induced by the microenvironment, or irreversible due to permanent alterations in the cancer cell itself. Study design: we will carry out these experiments using the estrogen dependent M05 mouse mammary tumor, and the stable cell lines derived from it, LM05-Mix (composed of both epithelial and fibroblastic cells) and the stable LM05-E (epithelial) and LM05-F (fibroblastic) clones. Aims 1 and 2 will be carried out using the stable cell lines and aim 3 will be achieved using passages of the M05 tumor that are sensitive and resistant to endocrine therapy. Potential outcomes and benefits: to date experimental work on hormone refractory breast cancer has been focused on the epithelium of the tumor. Our preliminary data suggest that the stroma may be key in determining whether or not a tumor is resistant to TAM. Our results will contribute to a better understanding of the biology of TAM resistant breast cancer and may impact the rational for the development of therapies which may consider modulating the tumor microenvironment.