Abstract 3424: Role of miR-489 in mammary gland development and Her2 mediated tumorigenesis

Abstract

Abstract HER2 overexpression is linked with poor prognosis and outcome in breast cancer. In our previous study, we have found miR-489 was specifically down regulated by HER2 overexpression. Restoration of miR-489 in multiple breast cancer cell lines significantly inhibited cell growth in vitro and decreased tumor growth in xenograft mice. To study role of miR-489 in Her2 mediated tumorigenesis, for the first time we generated MMTV-miR-489 transgenic mice, which overexpress miR-489 specifically in mammary gland. Our qRT-PCR data has confirmed transgenic mice have significantly more miR-489 expression than FVB mice. We used western blot to further validate our model system and found significant downregulation of miR-489 targets DEK and PTPN11. To find out whether miR-489 has any role in mammary gland development, mammary gland whole mount was performed from wild type FVB mice and MMTV-miR-489 mice at different age. Mammary gland from MMTV-miR-489 mice demonstrated reduction in growth at early age. Our immunohistochemistry staining demonstrated significantly reduction in Ki-67 positive cells in MMTV-miR-489 mammary gland at early age, further confirming reduced growth in MMTV-miR-489 mice. However, we found no significant effect on weight of litters of MMTV-miR-489 female since after 8-week mammary gland was able to recover growth. To find out effect of miR-489 overexpression on Her2 mediated tumorigenesis, we generated double transgenic mice MMTV-Her2/miR-489 by crossing MMTV-miR-489 mice with MMTV-Her2 mice. We have observed significant delay in tumor onset and reduced tumor growth in MMTV-Her2/ miR-489 mice compare to MMTV-Her2 mice. We have also observed less number of metastatic site in lung by performing H and E staining of lung. Our IHC data showed reduction in PTPN11 and DEK in miR-489 overexpress mammary tumor. Surprisingly, we found significant reduction of miR-489 expression in mammary tumors of MMTV-Her2-miR-489 when compared with normal mammary gland of same mice. Overall, our results indicated miR-489 overexpression suppresses mammary gland development at early age, reduced mammary tumorigenesis and decrease lung metastasis by targeting PTPN11 and DEK. Citation Format: Yogin Patel, Mithil Soni, Shou Liu, Hexin Chen. Role of miR-489 in mammary gland development and Her2 mediated tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3424. doi:10.1158/1538-7445.AM2017-3424