Many mechanisms have been attributed to de novo and acquired trastuzumab drug resistance in patients with HER2-enriched breast cancer; common mediated resistance is inactivation of the tumor suppressor gene PTEN seen in approximately 40% of patients. Evidence show the HER2 gene plays a significant role in regulating breast cancer stem cells through PTEN deletion; increasing evidence show these cancer stem cells may be responsible for drug resistance, cancer recurrence and metastasis. Studies demonstrate how PTEN deletion in HER2-overexpressing breast cancer activates an IL6 inflammatory feedback loop expanding the cancer stem cell population displaying EMT properties, conferring trastuzumab drug resistance and metastasis.
While new therapeutic approaches for targeting HER2-enriched tumors with PTEN deletion are in progress, further understanding of molecular systems involving EMT cancer stem cell expansion as well as of de novo and acquired trastuzumab drug resistance is important for improving therapeutic options. Our lab conducted RNA sequencing to further explore functional mechanisms behind this aforementioned molecular system and found the upregulation of mesenchyme homeobox 1 (Meox1) as a potential transcriptional factor regulator.
Meox1 is a non-cluster homeobox transcription factor expressed during embryonic development, critical in somite morphogenesis. Recent evidence has linked Meox1 as a critical PBX1 cofactor in ovarian cancer. As of yet, the role of Meox1 has never been studied in the context of breast cancer in correlation with cancer stem cells. Therefore specifically, the purpose of this study is to elucidate the molecular role of Meox1 in HER2-amplified PTEN-deleted trastuzumab-resistant breast cancer in order to provide functional and mechanistic insight involving EMT cancer stem cell expansion as well as of de novo and acquired trastuzumab drug resistance.
RT-qPCR analyses of Meox1 expression using different breast cancer cell lines show correlation between increase in Meox1 expression with PTEN deletion. In vitro studies show siRNA knockdown of Meox1 decreases cancer stem cell properties of both colony and mammosphere formation in the BT474 HER2-enriched breast cell line that is PTEN-deleted and long term trastuzumab treated. Furthermore, lentiviral stable overexpression of Meox1 in normal immortalized MCF10A breast cancer cell line shows an increase in mammosphere formation compared to control infections.
These preliminary results suggest Meox1 may be a critical transcription factor responsible for cancer stem cell progression in PTEN-deleted trastuzumab-resistant breast cancer. As such, further functional and mechanistic investigation of this homeobox transcription factor may provide additional understanding for de novo and acquired drug resistance and disease recurrence, potentially offering advanced therapeutic options.
Citation Format: Mari Gasparyan, Joseph P. Burnett, Lichao Sun, Duxin Sun. Determining the functional and mechanistic role of homeobox transcription factor Meox1 in breast cancer and breast cancer stem cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2509.