title: Co-overexpression of GEP100 and AMAP1 proteins correlates with rapid local recurrence after breast conservative therapy.
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.
authors.affiliation: Department of Radiation Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan.
authors.forename: Rumiko
authors.initials: R
authors.lastname: Kinoshita
authors.forename: Jin-Min
authors.initials: JM
authors.lastname: Nam
authors.forename: Yoichi M
authors.initials: YM
authors.lastname: Ito
authors.forename: Kanako C
authors.initials: KC
authors.lastname: Hatanaka
authors.forename: Ari
authors.initials: A
authors.lastname: Hashimoto
authors.forename: Haruka
authors.initials: H
authors.lastname: Handa
authors.forename: Yutaro
authors.initials: Y
authors.lastname: Otsuka
authors.forename: Shigeru
authors.initials: S
authors.lastname: Hashimoto
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Onodera
authors.forename: Mitsuchika
authors.initials: M
authors.lastname: Hosoda
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Onodera
authors.forename: Shinichi
authors.initials: S
authors.lastname: Shimizu
authors.forename: Shinya
authors.initials: S
authors.lastname: Tanaka
authors.forename: Hiroki
authors.initials: H
authors.lastname: Shirato
authors.forename: Mishie
authors.initials: M
authors.lastname: Tanino
authors.forename: Hisataka
authors.initials: H
authors.lastname: Sabe
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis*; D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D059248:Chemoradiotherapy; D003131:Combined Modality Therapy; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000096:biosynthesis*; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D015412:Mastectomy, Segmental / Q000379:methods; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D012044:Regression Analysis; D012189:Retrospective Studies; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: C117891:ASAP1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D020662:Guanine Nucleotide Exchange Factors; C504483:IQSEC1 protein, human