Recent progress in diagnostic tools allows more breast cancers being detected at early pre-invasive stage. This brings imposing demands on better understanding of early stage breast cancer progression and how it may develop into invasive and metastatic breast cancers. Recently, we discovered that 14-3-3zeta, a member of the 14-3-3 family proteins that are highly conserved through evolution and participate in many important cellular processes, is overexpressed in >45% of breast cancers and this overexpression predicts poor patient survival. The increased expression of 14-3-3zeta begins at the stage of atypical ductal hyperplasia (ADH), a relatively early stage in the progression towards breast cancer, and can be detected in about 56% ductal carcinoma in situ (DCIS). We have investigated the impact of high-expressing 14-3-3zeta on normal mammary epithelial cells (MECs) in a three-dimensional (3D) culture model that simulates in vivo conditions of acini formation in the mammary gland and has retained MEC interactions with basement membrane (BM). We found that in contrast to the normal acini structures of control virus-infected MCF10A MECs, increasing 14-3-3zeta expression by retroviral gene transfer in MCF10A led to disorganized acini structures that showed loss of polarity, increased proliferation, and filling of the luminal space which is a hallmark of early breast cancers, such as ADH and DCIS. Based on these novel findings, we hypothesize that 14-3-3zeta is involved in the early stages of transformation of normal MECs and plays important roles in the early progression towards breast cancer. In this proposal, we will use the 3D culture model to determine the role of high-expressing 14-3-3zeta in the early transformations of MECs by investigating whether increasing 14-3-3zeta in nonmalignant MECs or blocking 14-3-3zeta in transformed MECs will alter acini structures and key properties involved in acini formation, including MEC polarity, apoptosis, and proliferative suppression (Aim 1). Then, we will further dissect the molecular mechanisms/signaling pathways by which high-expressing 14-3-3zeta disrupts acini structures and induces early transformation of MECs (Aim 2). Finally, we will confirm the importance of 14-3-3zeta in breast cancer progression in tissues from patients with untreated early stage node-negative breast tumors (Aim 3). These comprehensive approaches will define the role of 14-3-3zeta in early stage breast cancer progression, which could impact the early detection, intervention, and treatment of breast cancer. This effort will ultimately lead to a decrease in breast cancer metastasis and mortality.
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