Abstract P4-11-24: TIF1[gamma] interacts with the TGFβ1/SMAD4 signaling leading to poorer outcome in operable breast cancer
Authors: Kassem Loay , Fattet Laurent , Lopez Jonathan , Thibault Goulvent , Lavergne Emilie , Chabaud Sylvie , Carrabin Nicolas , Chopin Nicolas , Bachelot Thomas , Gillet Germain , Treilleux Isabelle , Rimohk Ruth 
Published: May 2015

Abstract
Background
The Transforming growth factorβ (TGFβ) signaling has a paradoxical role in cancer development and outcome. It protects against tumorigenesis by inhibiting cell growth and promoting apoptosis, but at advanced stages, it promotes tumor progression. Besides, the prognostic significance of the TGFβ1, SMAD4 in breast cancer patients is also an area of many contradictions. Transcriptional intermediary factor 1γ (TIF1γ) is thought to interact with the TGFβ/SMAD signaling through different mechanisms. Our study aimed at defining the prognostic significance of TGFβ1, SMAD4 and TIF1γ expression in breast cancer patients in addition to detection of possible interactions among those markers that might affect the outcome and explain the contradictory results.
Methods
Immunohistochemistry was performed on TMA blocks prepared from samples of 248 operable breast cancer patients who presented at CLB between 1998 and 2001 using. The intensity and the percentage of stained tumor cells were integrated into a single score (0-6) and a cutoff was defined for high or low expression for each marker. Correlation was done between the TGFβ1, SMAD4 and TIF1γ expression with the clinico-pathologic parameters using Pearson’s chi-square test. Kaplan-Meier method was used to estimate distant metastasis free survival (DMFS), disease free survival (DFS) and overall survival (OS) and the difference between the groups was evaluated with log-rank test.
Results
223 cases were assessable for TIF1γ, 204 for TGFβ1 and 173 for SMAD4. Median age at diagnosis was 55.8 years (range: 27 to 89 years). Tumors were larger than 20 mm in 49.2% and 45.2% had axillary lymph node (LN) metastasis (N1a to N3). 19.4% of the patients had SBR grade I tumors, 46.8% grade II tumors and 33.9% grade III tumors. ER was positive in 85.4%, PR in 75.5% and Her2-neu was over-expressed in 10% of the cases. Nuclear TIF1γ, cytoplasmic TGFβ1, nuclear and cytoplasmic SMAD4 staining was high in 35.9%, 30.4%, 27.7% and 52.6% respectively. TIF1γ expression was associated with younger age (p=0.006), higher SBR grade (p&lt;0.0001), more ER negativity (p=0.035), and tumors larger than 2 cm (p=0.081), while TGFβ1 was not associated with any of the traditional prognostic factors.
TGFβ1 expression in tumor cells was a marker of poor prognosis regarding DMFS (HR=2.28; 95%CI: 1.4 to 3.8; p=0.002), DFS (HR=2.00; 95% CI: 1.25 to 3.5; p=0.005) and OS (HR=1.89; 95%CI: 1.04 to 3.43; p=0.037). TIF1γ expression carried a tendency towards poorer DMFS (p=0.091), DFS (p=0.143) and OS (p=0.091). In the multivariate analysis TGFβ1 remained an independent predictor of shorter DMFS, DFS and OS after adjustment for age, tumor size, SBR grade and LN invasion. Moreover, the prognostic significance of TGFβ1 was more obvious in the TIF1γ high patient subgroup than in the patients with TIF1γ low expression. The subgroup expressing both markers had the worst DMFS (HR=3.2; 95%CI: 1.7 to 5.9; p&lt;0.0001), DFS (HR=3.02; 95%CI: 1.6 to 5.6; p&lt;0.0001) and OS (HR=2.7; 95%CI: 1.4 to 5.4; p=0.005).
Conclusion
There is a crosstalk between the TIF1γ and the TGFβ1/SMAD4 signaling that deteriorate the outcome of operable breast cancer patients and when combined together they can serve as an effective prognostic tool for those patients.
Citation Format: Loay Kassem, Laurent Fattet, Jonathan Lopez, Goulvent Thibault, Emilie Lavergne, Sylvie Chabaud, Nicolas Carrabin, Nicolas Chopin, Thomas Bachelot, Germain Gillet, Isabelle Treilleux, Ruth Rimohk. TIF1[gamma] interacts with the TGFβ1/SMAD4 signaling leading to poorer outcome in operable breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-11-24.