HMGA2 mediates topoisomerase II inhibitors cytotoxicity in breast cancer cells

Abstract

2110 Background: The HMGA2 protein belongs to the architectural transcription factor HMGA family, which plays a role in chromosomal organization and transcriptional regulation. Ectopic overexpression of HMGA2 is known to be associated with neoplastic transformation in several human tumors. Clinically, HMGA2 expression in patients with breast cancer is an indicator for poor prognosis and metastasis. However, the precise role and molecular events mediated by HMGA2 in tumorigenesis and its relation to chemotherapy resistance still need to be defined. Methods: Pa-4 and HMGA2-expressing Pa-4/HMGA2 cells, 2 breast cancer cells (both ER and PR negative) with differential expression of HMGA2, HS578T and HCC1419 were used to test their sensitivity towards doxorubicin (DOX) and irinotecan (CPT11) in a dose-dependent manner. HS578T cells express higher endogenous level of HMGA2 than HCC1419. Results: Both DOX and CPT11-treatments was able to inhibit Pa-4 and Pa-4/HMGA2 cells in a dose-dependent fashion. Notably, DOX elicited a more pronounced cell killing in Pa-4/HMGA2 than Pa-4. However no marked differences were observed when CPT11 were used. Similarly, HS578T cells, which express higher level of endogenous HMGA2, were more sensitive to DOX than HCC1419 cells. Dox delays the G2/M transition in Pa-4 and Pa-4/HMGA2. Since DOX is knows to induce DNA double strand breaks, we examined the cellular responses to DOX-mediated genotoxicity. As expected, DOX-treatment led to a rapid and steady ATM S1981 and H2AX S139 phosphorylation in Pa-4 cells. Intriguingly, a persistent H2AX S139 phosphorylation was observed, resulting in subsequently modest DOX-mediated induction of H2AX phosphorylation in Pa-4/HMGA2 cells. Notably, both Pa-4 and Pa-4/HMGA2 were capable of elevating phospho-ATM levels in response to DOX to a similar level. Conclusions: We demonstrated that HMGA2 expression renders chemosensitivity towards DOX by modulating cellular response to genotoxicity in breast cancer cells, as evidenced by H2AX and ATM phosphorylation profiles. This mechanism may underlie HMGA2 mediated tumorigenesis and may be crucial to achieving a patient specific treatment outcome. No significant financial relationships to disclose.