Abstract
A major problem of current cancer research and therapy is prediction of tumor recurrence after initial treatment, rather than the simple biological characterization of the malignancy and proliferative properties of tumors. Breast conservation therapy (BCT) is a well-approved, standard treatment for patients with early stages of breast cancer, which consists of lumpectomy and whole-breast irradiation. In spite of extensive studies, only 'age' and 'Ki-67 positivity' have been identified to be well correlated with local recurrence after BCT. An Arf6 pathway, activated by GEP100 under receptor tyrosine kinases (RTKs) and employs AMAP1 as its effector, is crucial for invasion and metastasis of some breast cancer cells. This pathway activates β1 integrins and perturbs E-cadherin-based adhesions, hence appears to be integral for epithelial-mesenchymal transdifferentiation (EMT). We here show that expression of the Arf6 pathway components statistically correlates with rapid local recurrence after BCT. We retrospectively analyzed four hundred seventy-nine patients who received BCT in Hokkaido University Hospital, and found 20 patients had local recurrence. We then analyzed pathological samples of patients who experienced local recurrence by use of Kaplan-Meier analysis, Stepwise regression analysis and the t-test, coupled with immunostaining, and found that co-overexpression of GEP100 and AMAP1 correlates with rapidity of the local recurrence. Their margin-status, node-positivity, and estrogen receptor (ER)- or progesterone receptor (PgR)-positivity did not correlated with the rapidity. This study is the first to show that expression of a certain set of proteins correlates with the rapidity of local recurrence. Our results are useful not only for prediction, but highlight the possibility of developing novel strategies to block local recurrence. We also discuss why mRNAs encoding these proteins have not been identified to correlate with local recurrence by previous conventional gene expression profiling analyses.
Highlights
A major problem of current cancer research and therapy is prediction of tumor recurrence after initial treatment, rather than the simple biological characterization of the malignancy and proliferative properties of tumors
Local recurrence after Breast conservation therapy (BCT) has been reported to vary according to 5 molecular subtypes of breast cancer, that were classified based on their gene expression signatures [5,6]
By use of the Kaplan-Meier and Stepwise regression analysis [29], as well as the t-test, we found that the co-expression of GEP100 and AMAP1 proteins both at high levels correlates with the rapidity of local recurrence after BCT
Summary
A major problem of current cancer research and therapy is prediction of tumor recurrence after initial treatment, rather than the simple biological characterization of the malignancy and proliferative properties of tumors. Breast conservation therapy (BCT) is a well approved, standard treatment for patients with early stages of breast cancer [1,2,3], which consists of lumpectomy and whole-breast irradiation. Studies of relatively long years of follow-up have shown that 8.8 to 20% of breast cancer patients show local recurrence after BCT. Several factors, such as young age and high expression levels of Ki-67 antigen, a nuclear marker of cell proliferation, have been recognized to be risk factors for local recurrence after BCT [4]. Local recurrence after BCT has been reported to vary according to 5 molecular subtypes of breast cancer, that were classified based on their gene expression signatures [5,6]. Nodal status and tumor grades were reported to be correlated with local recurrence after BCT [7,8]
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