Abstract P6-01-20: A role of MACC1 expression and its regulation of the HGF/c-Met pathway in breast cancer

Background The newly identified gene, metastasis-associated in colon cancer 1 (MACC1), is suggested to be a transcriptional regulator of the receptor tyrosine kinase gene c-Met, leading to cancer progression and metastasis in colorectal cancer. Also in breast cancer, aberrant hepatocyte growth factor (HGF) / c-Met signaling has been shown to contribute to worse prognosis and confer resistance to endocrine therapy or trastuzumab treatment, however, little is known of the role of MACC1. Here, we report its impact on the survival for breast cancer patients and the biological function in the cell lines. Methods A total of 300 breast cancer patients who received both surgery and adjuvant treatment at Kumamoto University Hospital between 2001 and 2009 were selected. We analyzed expressions of MACC1 by reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry (IHC) to evaluate the associations of its expression with breast cancer survival. In an in vitro study, the expressions of MACC1 were examined by Western blotting in breast and colorectal cancer cell lines. After transfection with a MACC1-harboing plasmid, we evaluated the activities of cMet protein and cell motility and proliferation. Further, the binding ability of MACC1 to the cMet promoter was evaluated using chromatin immunoprecipitation (ChIP) assay. Results In survival analyses, reduced MACC1 expressions were associated with patient mortality. Cox proportional hazards model showed that MACC1 mRNA (HR = 0.25, P = 0.001), MACC1 protein (HR = 0.37, P = 0.016), as well as axillary nodal status and estrogen receptor status, were independent predictors of mortality. No significant correlations between MACC1 expression and other clinicopathological factors were found. We found no strong positive correlation between MACC1 protein and c-Met mRNA expression with a Spearman’s coefficient of 0.16 (P = 0.0067). In the cell lines tested, MACC1 expression was much higher in colorectal cancer cells (DLD-1) than breast cancer cells (MCF7 and MDA-MB-231). To investigate the impact of MACC1 on the biological function of the cells, we transfected with MACC1 in breast cancer and colorectal cancer cells (SW480). MACC1 overexpression did not induce cMet expression in MCF7, whereas the corresponding cMet expression was upregulated in SW480 cells. Further, SW480 cells transfected with MACC1 showed enhanced migratory ability, whereas in MDA-MB-231 cells, transfection of MACC1 had no impact on this ability. In ChIP assay, the binding of MACC1 to the cMet promoter region was suggested in SW480 cells, but not in MCF7 cells. Conclusions Our findings provide some novel insights into the role of MACC1 for breast cancer, indicating that it plays different roles in breast cancer and in several other cancers. The biological mechanism of MACC1 which underlies improvement of breast cancer prognosis remains unelucidated. There is possibility that MACC1 does not act as the exclusive master regulator of the HGF/c-Met signaling involved in disease progression in breast cancer. Further studies to validate our results are needed. Citation Format: Aiko Sueta, Yutaka Yamamoto, Mitsuhiro Hayashi, Takashi Takeshita, Mutsuko Ibusuki, Hirotaka Iwase. A role of MACC1 expression and its regulation of the HGF/c-Met pathway in 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 P6-01-20.