The Importance of EMT in Breast Cancer in African American Women

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DESCRIPTION (provided by applicant): Our laboratory has discovered a gene, BP1, that is activated in 89% of the tumors of African American women (AAW), compared with 57% of the tumors of Caucasian women (CW). High level BP1 expression is associated with aggressive and larger tumors. Tumors of AAW are also aggressive - higher grade, larger, more frequently estrogen receptor (ER) negative, and more proliferative - resulting in an almost 50% higher mortality rate of AAW than CW with breast cancer. BP1 may also be involved in a process called the epithelial to mesenchymal transition (EMT), which is associated with transdifferentiation of malignant epithelial cells to mesenchymal cells. BP1 up-regulates the Twist gene, an inducer of EMT. EMT plays a role in breast cancer progression, invasion, metastasis, and drug resistance, making it a potential therapeutic target. Clinical studies indicate that EMT is predictive of poor outcome in many tumors. Together, these data suggest that EMT may be more frequent in tumors of AAW than CW: expression of BP1 may activate Twist, causing EMT and, independently, other genes may induce EMT, resulting in the more aggressive tumors seen in AAW. HYPOTHESES. We hypothesize that: (a) the breast tumors of AAW undergo EMT more frequently than tumors of CW, and (b) high level BP1 expression is associated with EMT. SPECIFIC AIMS. Aim 1. To determine the frequency of EMT in the tumors of AAW and CW. Aim 2. To determine the involvement of BP1 in EMT. APPROACH. Markers of EMT will be examined in 50 tumor tissues from AAW and 50 tumor tissues from CW, matched for age and stage of breast cancer. Immunohistochemistry will be used to determine the expression of EMT markers, including E-cadherin, vimentin, and Twist. Data will be correlated with clinico- pathological data available for all patients. The same markers will be measured in RNA from a subset of the tumors for which tissue is available. To discover the involvement of BP1 in EMT, the tissues and RNA samples described above will also be assessed for BP1 levels. Breast cancer cell lines derived from the tumors of AAW and CW will be studied to determine the levels of BP1 and markers of EMT. Selected cell lines expressing either low or high levels of BP1 will be used to (i) overexpress BP1 or (ii) repress BP1, respectively, followed by measurement of E-cadherin, vimentin and Twist levels. Microarrays will be used to identify additional changes in gene expression associated with BP1 and EMT. Additional assays will include measurement of invasion and migration, and observation of morphological changes after overexpression or reduction of pBP1. SIGNIFICANCE. If EMT is more prevalent in tumors of AAW than CW, genes expressed during the transition would make good targets for therapy, with the possibility of reducing or preventing metastases. If BP1 is a regulator of EMT (through Twist), there would be a strong rationale for targeting BP1 using small molecule inhibitors, siBP1 or other approaches. PUBLIC HEALTH RELEVANCE: If EMT is more prevalent in tumors of AAW than CW, genes expressed during the transition would make good targets for therapy, with the possibility of reducing or preventing metastases. If BP1 is a regulator of EMT (through Twist), there would be a strong rationale for targeting BP1 using small molecule inhibitors, siBP1 or other approaches.