Molecular Regulation of Breast Cancer Progression Cancer of the breast (BrCa) is the most frequent tumor in women, affecting black women most severely, with military women at increased risk of BrCa. Mortality and morbidity are due to spread and metastasis. Localized primary carcinomas are often removed, with curative effect for up to 80%. Once the cancer has disseminated, current therapies, even newer biologics, prolong life for just a few years. Dissemination leads to morbidity and mortality even in 10-30% of women deemed cured. The signals that enable metastatic survival and outgrowth of these disseminated tumors are critical transition points, and the focus of our past and ongoing studies. Our investigations during the present and previous Award periods demonstrated that upon dissemination to the ectopic microenvironment, the parenchymal cells direct the tumor cells to re-express epithelial markers including the defining E-cadherin. This cell-cell cohesion marker forms heterotypic binding that renders the tumor cells more resistant to killing by chemotherapies and death cytokines. Ongoing experiments have shown that this protection from death signals proceeds through E-cadherin-triggered signaling. Ominously, this epithelial reversion also likely leads to tumor cell dormancy, a dreaded complication of tumor dissemination. The quiescence of dormancy is likely only partly responsible for the chemoresistance, as initial studies have found that E-cadherin protects even cycling cells from chemotherapy. We have modeled this to demonstrate that proliferative quiescence underlies the dormancy, but that this non-proliferative state is plastic with stimulated cells being `awakened' and regaining an aggressive mesenchymal phenotype, thus growing into clinically evident metastases. We and others have indications that activation of the supporting nonparenchymal cells by stressors leads to outgrowth that will be investigated herein. Thus, our foundational model posits that E-cadherin-ligandation signals promote tumor cell survival via select intracellular pathways that can be targeted to reverse the chemoresistance. Further, the dormancy of these cryptic micrometastases, that partially protect the tumor cells, can be reversed by stressors activating stromal, immune and endothelial cells in the tissue. By discerning the operative signals and pathways we can develop novel approaches to micrometastases in targeting the emergent breast cancer cells. Thus, we hypothesize that the interplay of the tumor cells with cells of the metastatic microenvironment dictate both responsiveness to tumor targeted therapies and dormancy/outgrowth. This hypothesis now leads to three linked questions - what are the mechanisms that confer the chemoresistance of metastasis, why do the tumor cells then later emerge from this dormant stage to grow as lethal disseminated tumors, and can these emergent carcinoma cells be targeted, as explored by: I. Defining the key tumor cell signaling nexi downstream from E-cadherin that provide for resistance to killing in the micrometastatic niche. II. Determining whether activation of liver nonparenchymal cells trigger emergence from dormancy. III. Determining whether targeting mesenchymal carcinoma cells limits outgrowth of emergent carcinoma cells. The successful completion of these experiments will shed new light on unexpected molecular controls of cell behavior that are subverted in breast carcinoma to promote progression. These studies test novel hypotheses using state of the art techniques. Validation of even components of our foundational model and our initial translational effort would highlight future avenues for rational interventions for the therapeutically refractory stage of cancer, clinically undetectable micrometastases. In the more immediate term, the findings would impact the choice of alternative approaches, in that therapeutic regimens aimed at metastatic cancer would include agents designed to keep cells in stasis in addition to attacking those that exit quiescence.
Breast cancer plagues military women (and even men) to a greater degree than the civilian population, and women of color also more severely. Breast cancer in military and veteran women is so devastating that a number of bills have been forwarded to directly address this occurrence. Our proposal will focus on the metastatic disease that directly leads to mortality and is resistance to current therapies. Even partial support of our hypothesis would suggest new diagnostic and therapeutic approaches to disseminated cancer, and novel insights to treat cryptic disseminated disease even attacking dormant cells or reverting resistant tumors to sensitive ones. Longer term, new targets would be defined.
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