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Mechanical Stress: an unexplored factor in regulation of cell signaling in DCIS and early breast cancer progression
Breast cancer death is caused by invasive and metastatic cancer that is preceded by a pre-invasive stage, ductal carcinoma in-situ (DCIS). DCIS represents a key target for strategies to prevent invasive breast cancer. Cellular stress is likely to be a prominent factor within neoplastic epithelium, and particularly in pre-invasive breast lesions. Mechanical stress, with both compression and sheer forces caused by cell crowding and constriction by an abnormal fibrotic stroma, is one of the forms of stress that could also be present, has been implicated as an important factor in tumor biology, but has not been considered in this context. My goal is to use in-vitro breast cell models to confirm that mechanical stress can influence epithelial breast cell gene expression, and then to identify specific gene markers of mechanical stress in these models that are distinct from at least one other form of stress commonly present, hypoxic stress, and then to validate these markers in vivo in breast biopsy tissues to begin to establish the presence and extent of mechanical stress as a factor in DCIS. I propose to explore an unbiased approach to identify mechanical stress response marker genes and also to explore a specific candidate regulator, Jab1 that may coordinate some aspects of this cellular response. My overall hypothesis is that mechanical stress can directly modulate epithelial gene expression and that this stress occurs in DCIS and may serve as an independent factor that promotes tumor progression. Specific aims: 1) To determine if mechanical stress directly regulates breast epithelial gene expression and to identify specific marker genes of mechanical stress in breast cancer; 2) To explore the possible role of Jab1 as a key mediator of the signal transduction pathways related to mechanical stress and the relation of this stress response to the wound-response signature in breast cancer; 3) To validate candidate mechanical stress response marker genes by measuring gene expression in DCIS lesions within breast tissue biopsies to confirm that they can be expressed in vivo. The innovative nature of my training plan will provide me with novel observations about mechanical stress and intracellular signals in ductal carcinoma in situ (DCIS) to develop further as an independent investigator. I will use established 2D , and to be developed novel 2D or 3D in-vitro breast cell models to test the effect of forces on gene expression, particular to Jab1 and I will evaluate and validate candidate markers of mechanical force stress response in-vivo using human breast tissues and DCIS lesions. These studies have the potential to lead to new understanding around a critical clinical issue, the management of DCIS, and to identify new functional markers of risk of progression related to a relatively unexplored factor, mechanical stress .
Breast cancer is the second most common cause of cancer related deaths in women in North America. Breast cancer starts in the ducts (known as the DCIS stage). DCIS is described by several terms such as pre-cancerous, pre-invasive, non-invasive, because the abnormal cancer cells stay inside the milk ducts and at this stage are not yet able to spread to other parts of the breast or body. So a woman cannot die until the cancer progresses from this DCIS stage to the invasive stage. DCIS is the ideal target in a strategy to prevent invasive breast cancer. The project is therefore focused on DCIS, because of its scope for development of new treatments and prevention for women cancer, its significance in basic mechanisms of cancer biology and the need for new ideas and concepts and model systems for its study. Mechanical stress has the potential to strongly influence a large number of cellular processes associated with tumor growth and invasion. DCIS is a critical stage for breast cancer invasion. In wound healing, mechanical force may persist to cause pathological scarring and contributes to epithelial?mesenchymal transition (EMT). The acquisition of invasive cellular properties in human cancers has been associated with EMT. Cancers have long been described as wounds that do not heal, suggesting that the two processes share common features. Recently, modern genomic and proteomic methods have confirmed that features of the molecular program of normal wound healing might play an important role in cancer metastasis and a "wound-response signature" displayed by cancers reveals links between wound healing and breast cancer progression. A master regulator of this wound response signature is a gene called Jab1. My objective is to understand if and how mechanical stress signals are converted into the intracellular signals that regulate Jab1 in ductal carcinoma in situ (DCIS) and in invasive breast carcinomas to contribute to breast tumor progression. I propose a novel hypothesis to examine the possible role of mechanical stress on cancer cells because I believe that this factor has not been considered before and may open new opportunities to understand what causes the progression of breast cancer from the DCIS to invasive stage. The project I propose will first explore what genes are altered by mechanical stress in breast cancer cells studied in 2-dimensional and 3-dimensional models, then identify genes that are specifically altered by mechanical stress but not by other forms of stress that are known to exist in cancer tissues such as lack of oxygen, and then show if these genes can be used to measure mechanical stress in DCIS lesions. My project also incorporates multiple techniques used at various stages, including Microarray and tumor bank resources. Emphasis is put on potential clinical implications in DCIS and the ultimate goal is to blend breast cancer research with changes in clinical practice to improve outcomes of women with breast cancer.