Candidate, Career Development Plan and Environment: The Candidate is a postdoctoral fellow transitioning to Assistant professor of Research at University of Colorado Anschutz Medical Campus (AMC, sponsoring institution). Her goal is to establish and direct an extramurally funded laboratory at a University level research institution and most immediately, to transition to a fully independent position in the next 3 years. Her background, research experience and record of publications demonstrate her commitment to a career in cancer research, her suitability to conduct these studies, and her ability to conduct innovative and highly translational research. The career development plan and proposed studies were designed to provide the candidate with the skills, experiences and salary support necessary to independently perform research studies examining the underlying mechanisms of hormonal regulation of metastatic disease in the CNS. This plan will consolidate the candidate's expertise and produce high impact publications and preliminary data to be competitive for R01 funding. The candidate counts with strong support from her mentors and team of collaborators, as well as strong institutional commitment to her career development. The candidate's institution is a NCI-designated Cancer Center with an outstanding breast cancer research group and exceptionally equipped facilities. The research environment is optimal to support both the research plan and the candidate's career. Research plan: Brain metastases represent a substantial health care problem in cancer patients. Ten to 16% of patients with metastatic breast cancer develop symptomatic brain metastases and ~80% die within one year of diagnosis. The absence of estrogen receptor (ER) expression in breast tumors that frequently metastasize to the brain has led to the neglect of studies on the role of hormone signaling in the progression of breast cancer brain metastasis. Primary and metastatic ER- breast cancers are not treated with anti-estrogen therapies since it assumed they are ineffective. However, preliminary data shows that 17-?-estradiol (E2) induces upregulation of EGFR ligands by astrocytes, cells that surround and infiltrate brain metastasis. Furthermore, brain metastatic cell lines show increased migration and proliferation in response to E2-treated astrocytes. Since EGFR is overexpressed in brain metastatic breast tumors and its activation is a known driver of invasion, migration and metastasis, it is hypothesized this is one of the mechanisms by which E2-induced paracrine signaling contributes to the brain metastatic ability of ER- breast cancers. Steroid hormones produced by gonads or adrenals cross the blood brain barrier, and are also produced locally by aromatase expressed in neurons and astrocytes. Importantly, aromatase inhibitors and anti-estrogens used for the treatment of ER+ tumors can cross the blood brain barrier and could be useful for treatment of all metastatic brain tumors because of their effects on the brain microenvironment. This proposal will test the novel hypothesis that estrogen-mediated responses of the brain microenvironment, particularly mediated by astrocytes, contributes to metastases progression independently of tumor ER status, and that anti-estrogen therapies will effectively treat brain metastases.
Aim 1 will test the hypothesis that E2 activates genomic ER- dependent responses in astrocytes, leading to the secretion of growth factors that affect brain metastases.
Aim 2 will elucidate the mechanism(s) by which estrogen-stimulated astrocytes increase brain-metastatic breast cancer invasion, migration and proliferation.
Aim 3 will test the hypothesis that E2 contributes to brain metastatic colonization by ER- breast cancer cells in vivo. !

Public Health Relevance

Brain metastases represent a particularly devastating outcome of cancer due to their effects in mortality and quality of life. Chemotherapeutic agents cannot cross the blood-brain barrier (thus, they do not reach the brain metastasis) and have threatening side effects. This proposal is unique because it tests the novel hypothesis that estrogen increases the metastatic potential of breast cancer cells in the brain by acting on the brain microenvironment. If this hypothesis is correct, clinically available anti-estrogen drugs -with lower side effects than chemotherapeutic drugs and able to reach the brain-, could soon be used for the treatment of brain metastases not only from breast, but also from other malignancies. The written critiques of individual reviewers are provided in essentially unedited form in this section. Please note that these critiques and criteria scores were prepared prior to the meeting and may not have been revised subsequent to any discussions at the review meeting. The Resume and Summary of Discussion section above summarizes the final opinions of the committee.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Career Transition Award (K22)
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Subcommittee G - Education (NCI)
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Wali, Anil
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University of Colorado Denver
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