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    Awarded Grants
    The Role of Osteoprotegrin-Ligand in Progesterone-Dependent Mammary Morphogenesis and Tumorigenesis

    Scientific Abstract:
    The progesterone receptor knockout (PRKO) mouse demonstrated that loss of P-induced proliferation results not only in a defect in mammary morphogenesis but also in a decrease in mammary tumor susceptibility. In the normal breast, mammary epithelial cells (MECS) that undergo proliferation in response to P do not express PR but closely align with MECS which do. This finding suggests P projects its proliferative effects via a paracrine mechanism of action in the normal breast; this segregation pattern for PR expression and proliferation is also conserved in the human. Derailment in this segregation pattern is expected to adversely affect normal P-induced breast growth. Indeed, a human breast tumor subgroup exhibit colocalization of ER/PR expression with proliferation, suggesting that a switch from a paracrine to an autocrine loop is an early event in tumorigenesis. Progress in understanding P’s paracrine effects in the breast was made with the finding that osteoprotegrin ligand (OPGL), a key signal in osteoclast differentiation, is induced by P in PR positive MECS. Based on the foregoing, we propose that OPGL acts as a paracrine mediator of the P-proliferative signal in the normal breast and that derailment of this signal results in breast cancer. To test this hypothesis, we will determine: 1) whether OPGL can rescue the PRKO mammary defect; and 2) whether the indiscriminate targeting of OPGL to the breast elicits breast cancer. Aim 1 will use the tetracycline regulated expression system to temporally control OPGL expression in the mammary epithelium of the PRKO. With the availability of a novel PR-knockin mouse, in which the reverse tetracycline transactivator is targeted to the PR gene, OPGL expression from a tetracycline-responsive transgene will be induced only in PRKO MEC lineages that would have expressed PR in the normal breast. Using a transgenic mouse in which OPGL expression is targeted to the mammary epithelium by the mouse mammary tumor viral promoter, aim 2 will test whether the indiscriminative targeting of the OPGL signal leads to cancer. This aim will address whether break-down of the segregation pattern for this effector pathway can cause breast cancer. Not only will these studies further our understanding of P's action in the normal breast but will also provide insight into P's role in breast cancer.

    Lay Abstract:
    Utilizing a mutant mouse (the PRKO), which is insensitive to the effects of progesterone (P), we demonstrated that P is not only essential for normal breast growth but is also required for breast cancer onset. This finding not only agrees with past epidemiological studies but also recent clinical trials, which reveal that combined estrogen (E)-P hormone therapy increases breast cancer risk beyond that observed for E treatment alone. To further understand the role of P during breast development and cancer, it will be imperative to identify target genes that are regulated by P in the breast. Toward this end, we showed that osteoprotegrin ligand (OPGL), a key protein in bone growth control, was induced by P in the mouse breast. As further support for OPGL as a molecular target for P action in the breast is: a) OPGL is only expressed in a specific cell-type of the breast that specifically receives the P signal; and b) OPGL is not expressed in the PRKO breast. Of clinical importance, OPGL has been detected in human tumors suggesting that OPGL expression may confer upon cancer cells a selective growth advantage and/or an ability to undergo metastasis to other target sites such as bone; this latter suggestion is based on OPGL’s previously reported bone resorbing functions. Based on the above, we hypothesize that OPGL mediates the P growth signal in the normal breast; this hypothesis predicts that abnormal expression of OPGL would lead to breast cancer. To test this hypothesis, we will evaluate: 1) whether OPGL can functionally replace P in the PRKO breast; and 2) whether inappropriately expressing OPGL in the absence of P control can elicit breast cancer. In aim 1, we will install the OPGL signal into the PRKO breast in order to rescue its growth defect due to P insensitivity. Using state-of the-art genetics, OPGL will be expressed only in cells of the PRKO breast that would have received the P signal if they had not become insensitive to this hormone. In aim 2, we will target OPGL expression to all cells of the breast to determine whether indiscriminate expression of OPGL in the absence of P control can lead to breast cancer. The above innovative studies, designed to examine OPGL’s relevance to the breast’s growth responses to P, will not only provide important information on how P exerts its effects during breast growth and cancer but may also aid in the design of novel diagnostic approaches and/or therapies for the future treatment and prevention of breast cancer.