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    Invasive Breast Cancer: HBP1 as a Clinical and Molecular Predictor

    Scientific Abstract:
    Background: Mammography has improved detection of early breast cancers, particularly DCIS and invasive breast cancer (IBC). IBCs have increased proliferation, invasiveness, and uncertain prognosis due to few markers and poor understanding of mechanisms. We focus on the HBP1 transcriptional repressor in IBC. HBP1 regulates the G1 phase of cell cycle progression and inhibits the Wnt signaling pathway (linked to breast and other cancers). Initial results from tumor samples identify loss-of-function HBP1 variants exclusively associated with IBC. Additionally, HBP1 regulates invasiveness in breast cells. Thus, analysis of HBP1 may illuminate ill-defined regulatory pathways that lead to invasiveness. Hypothesis: HBP1 is hypothesized to be a marker of IBC in the context of critical clinical and molecular parameters. IBC is largely characterized by morphology with uncertain prognosis, thus the definition of molecular tools will aid in classification of IBCs. Aims: 1) Definition of HBP1 as a marker for IBC. Expanded clinical screening will investigate HBP1 as a marker of fully invasive ductal carcinoma, and correlate HBP1 variants with lymph node status and with lymphovascular invasion. 2) HBP1 and gene networks for invasion. Increased proliferation and invasion are two features of IBC, with HBP1 linked to both processes. New and existing HBP1 variants from Aim 1 will be analyzed for regulation of invasiveness, with an emphasis on Wnt pathway regulation. Design: Aim 1- investigate correlation of HBP1 variants to invasive ductal carcinoma with a study of appropriate statistical power. Strikingly, HBP1 variants correlate with pure invasive disease, but not with mixed tumors with both DCIS and invasive pathologies. Thus HBP1 may reside between acquisition of full invasiveness and lymph node metastasis—a critical stage in breast cancer, for which there are few molecular clues. Other correlations (e.g. lymphovascular invasion, lymph node status, gene signatures in IBCs) will also be addressed. Aim 2- analyze the molecular function of the HBP1 variants and the signaling pathways regulating IBC, with an emphasis on the Wnt signaling pathway for HBP1 function. Secondly, the gene networks that are regulated by HBP1 and which control the invasive phenotypes will be defined. Outcomes/Benefits: These studies combine clinical correlation and molecular investigations to understand how the HBP1 gene may regulate IBC, which is a clinically vexing disease with uncertain prognosis. Our work should contribute to improving patient outcome by identifying new prognostic targets for IBC.

    Lay Abstract:
    Invasive breast cancer is an increasingly frequent diagnosis due to increased mammography surveillance. Invasive, or infiltrating ductal carcinoma, is generally locally invasive to the duct. These cancers may also have lymphovascular invasion and lymph node metastasis. However, invasive breast cancer has an uncertain prognosis and clinical course. This reveals a major gap in knowledge for prognosis. Thus a better understanding of the players that regulate invasive breast cancer should lead to improved prognostic, therapeutic, and preventative tools for breast cancer. Two characteristics of invasive breast cancer are increased proliferation and invasiveness. Ongoing and previous work suggests that the HBP1 gene has a role in both processes. One function of HBP1 is suppression of the Wnt oncogenic pathway. In some human breast cancers, an active Wnt pathway correlates with poor prognosis. In a first study of HBP1 in breast cancer, and consistent with an activated Wnt phenotype, we have isolated loss-of-function HBP1 variants at a relatively high rate. The clinical profile of these HBP1 variants strongly correlates to pure invasive breast cancer, with appearance in node-positive and node-negative disease. These data place HBP1 in a critical transition between tumor invasiveness and lymph node involvement. Thus the goal is to transition towards clinical applications, and in the future configuring follow-up patient studies. Thus, the first clinical studies must be solid and build a coalition of clinicians and researchers. The first clinical observations motivated expanded clinical and laboratory studies on the unexpected role of HBP1 in invasive breast cancer. The first step will solidify the clinical correlation of HBP1 variants with invasive breast cancer. These studies will identify tumor types and cases for later follow-up studies for progression and recurrence. We will also investigate whether HBP1 variants define a known or unique breast cancer type and whether there may be mutational hotspots for future diagnostic applications. The second step will use these breast-cancer associated HBP1 variants as powerful tools to understand how HBP1 might regulate invasiveness. Because of known HBP1 functions and recent reports, the role of the Wnt pathway in regulating invasiveness will be investigated. Together, the hope is to advance the clinical and molecular knowledge of invasive breast cancer, particularly the ill-defined stage between invasiveness and lymph-node metastasis, and to contribute to improving the outcome for invasive breast cancer.