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Down-Regulation of LATS1 and LATS2 mRNA Expression by Promoter Hypermethylation and Its Association with Biologically Aggressive Phenotype in Human Breast Cancers

Department of Surgical Oncology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan

Requests for reprints: Shinzaburo Noguchi, Department of Surgical Oncology, Osaka University Graduate School of Medicine, 2-2-E10 Yamada-oka, Suita, Osaka 565-0871, Japan. Phone: 81-6-6879-3772; Fax: 81-6-6879-3779; E-mail: noguchi{at}onsurg.med.osaka-u.ac.jp.

Purpose: LATS1 and LATS2 are tumor suppressor genes implicated in the regulation of cell cycle. Methylation status of the promoter regions of these genes as well as its correlation with their mRNA levels were studied in human breast cancers. Correlation of LATS1 and LATS2 mRNA levels with clinicopathologic characteristics of breast tumors were also studied.

Experimental Design: Methylation status of promoter regions of LATS1 and LATS2 was studied by a methylation-specific PCR and mRNA expression levels of LATS1 and LATS2 were determined by a real-time PCR assay in 30 breast cancers. In addition, correlation of LATS1 and LATS2 mRNA levels with clinicopathologic characteristics was studied in 117 breast cancers.

Results: Methylation-specific PCR showed that of 30 tumors, LATS1 promoter region was hypermethylated in 17 tumors (56.7%) and LATS2 promoter region was hypermethylated in 15 (50.0%) tumors. LATS1 mRNA levels in breast tumors with hypermethylation (2.15 ± 0.37, mean ± SE) were significantly (P < 0.01) lower than those without hypermethylation (6.09 ± 1.38), and LATS2 mRNA levels in breast tumors with hypermethylation (1.42 ± 0.66) were also significantly (P < 0.01) lower than those without hypermethylation (3.10 ± 1.00). The decreased expression of LATS1 or LATS2 mRNA was significantly associated with a large tumor size, high lymph node metastasis, and estrogen receptor and progesterone receptor negativity. Furthermore, the decreased expression of LATS1 mRNA, but not LATS2 mRNA, was significantly (P < 0.05) associated with a poor prognosis.

Conclusions: Hypermethylation of the promoter regions of LATS1 and LATS2 likely plays an important role in the down-regulation of their mRNA levels in breast cancers, and breast cancers with a decreased expression of LATS1 or LATS2 mRNA levels have a biologically aggressive phenotype.

Key Words: LATS1 • LATS2 • Hypermethylation • Breast Cancer • Prognosis

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