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Objectives: The high-mobility group A protein 1a (HMGA1a) protein is known as a transcription factor that binds to DNA, but recent studies have shown it exerts novel functions through RNA-binding. We were prompted to decipher the mechanism of HMGA1a-induced alternative splicing of the estrogen receptor alpha (ERα) that we recently reported would alter tamoxifen sensitivity in MCF-7 TAMR1 cells.Methods: Endogenous expression of full length ERα66 and its isoform ERα46 were evaluated in MCF-7 breast cancer cells by transient expression of HMGA1a and an RNA decoy (2′-O-methylated RNA of the HMGA1a RNA-binding site) that binds to HMGA1a. RNA-binding of HMGA1a was checked by RNA-EMSA. In vitro splicing assay was performed to check the direct involvement of HMGA1a in splicing regulation. RNA-EMSA assay in the presence of purified U1 snRNP was performed with psoralen UV crosslinking to check complex formation of HMGA1a-U1 snRNP at the upstream pseudo-5′ splice site of exon 1.Results: HMGA1a induced exon skipping of a shortened exon 1 of ERα in in vitro splicing assays that was blocked by the HMGA1a RNA decoy and sequence-specific RNA-binding was confirmed by RNA-EMSA. RNA-EMSA combined with psoralen UV crosslinking showed that HMGA1a trapped purified U1 snRNP at the upstream pseudo-5′ splice site.Conclusions: Regulation of ERα alternative splicing by an HMGA1a-trapped U1 snRNP complex at the upstream 5′ splice site of exon 1 offers novel insight on 5′ splice site regulation by U1 snRNP as well as a promising target in breast cancer therapy where alternative splicing of ERα is involved.

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Background: Breast cancer is a worldwide problem which urgently requires solution, in many countries still being the most common cause of malignancy associated death. The screening program aims to detect early breast cancer to improve survival. We investigated the clinicopathrogical characteristic including intrinsic subtypes and outcome of patients with screen-detected invasive breast cancer (S-DIBC) compared with those with symptomatic invasive breast cancer (SIBC). Material and Methods: From January 2005 to December 2011 840 patients with invasive breast cancer who underwent surgery at our hospital were included. There were 195 S-DIBCs and 645 SIBCs. We retrospectively reviewed the clinical and pathologic data. Ki-67 LI was categorized as low (<14%) and high (> or = 15%). Tumors were classified into four groups based on the expression of ER, PgR, Ki-67 and HER2 as follows: luminal A (ER+ and/or PR+, and HER2− and Ki67 low), luminal B (ER+ and/or PR+, and HER2+ or Ki67 high), HER2 disease (ER−, PR−, HER2+), and triple negative (ER−, PR−, HER2−). Overall survival (OS) and relapse-free survival (RFS) curves were generated using the Kaplan- Meier method. Survival comparisons were made with the log-rank test, the level of significance was taken to be 0.05. SPSS 18.0 software package was used for statistical analysis. Results: S-DIBC was associated with smaller tumor size, less lymph node involvement, and earlier stage compared with SIBC (P < 0.001). Significantly more tumors were positive for hormone receptors in the S-DIBC group as compared to the SIBC group (ER+,83.5% vs.75.1%, p = 0.017; PgR+, 73.4% vs. 60.6%, P = 0.009), with a greater proportion of the luminal A subtype in the S-DIBC group (S-DIBC: Luminal A 59.0%, Luminal B 25.6%, HER2 disease 4.6%, triple negative 10.8%; SIBC group: Luminal A 46.5%, Luminal B 30.0%, HER2 disease 6.6%, triple negative 16.8%). Patients with S-DIBC had better prognosis [5-year OS: 100% (S-DIBC) vs. 95.5% (SIBC), p = 0.005, 5-year RFS: 98.5 vs. 92.1%, p = 0.004]. Tumors detected with screening generally had more favorable outcomes than symptomatic cancers regardless of subtypes [5-year OS: (S-DIBC) Luminal A 100%, Luminal B 100%, HER2 disease 100%, triple negative 100%; (SIBC) Luminal A 95.9%, Luminal B 93.3%, HER2 disease 95.5%, triple negative 84.1%)]. Conclusions: Our results suggest that subtype distribution of S-DIBC differs from that of SIBC. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-02-05.

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Background Sentinel lymph node biopsy (SLNB) is accepted as a method in patients with clinically negative axillary lymph nodes because it was assumed to be associated with improvement of upper limb morbidity. The purpose of this study was to investigate that SLNB reduces upper limb morbidity of patients with breast cancer compared with axillary lymph node dissection (ALND). Methods The study comprised 362 patients with breast cancer who underwent measuring the upper limb mobility before and after surgery (at discharge, 1 month and 3 months after surgery). 241 patients underwent SLNB, 121 patients underwent ALND. In the SLNB group, 148 patients (48.1%) underwent breast conserving surgery (BCS), 67 patients (18.5%) underwent mastectomy. In the ALND group, 68 patients (18.8%) underwent BCS, 53 patients (14.6%) underwent mastectomy. Upper limb mobility was measured by the difference of the angle of the flexion and the angle of abduction between before and after surgery. The recovery defined that the difference of the angle between before and after surgery, is within 10 degree. The recovery rate was investigated by Kaplan-Meier method, and comparisons were evaluated using the log-rank test. Results The recovery rate of patients in the SLNB group was 85% in measuring flexion, 90% in measuring abduction 3 month after surgery. The recovery rate of patients in the ALND group was 52% in measuring flexion, 58% in measuring abduction. The recovery rate of upper limb function increase by SLNB than by ALND (P<0.001).’ Conclusions SLNB reduces upper limb morbidity of patients with breast cancer compared with ALND. SLNB can improve activity of daily life (ADL) by improving of the upper limb function. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-14-01.