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Breast cancer study in NEU transgenic mice (Bachelor thesis)

Κέκου, Ειρήνη/ Kekou, Eirini

Breast cancer is a complex disease, whose development and progression are determined by the combined action of different genetic and epigenetic alterations. Important oncogenic factors include the HER2/NEU receptor and the MYC transcription factor, which activate distinct yet overlapping molecular pathways that affect cell proliferation, survival, and mammary tumor progression. In parallel, alterations in other important regulators of cellular function, such as the activating Pik3ca H1047R mutation and the loss or dysfunction of the ARID1A chromatin remodeling epigenetic factor, have been associated with the development and progression of different cancer types. The purpose of this study is to investigate the effect of ARID1A loss and the activation of the Pik3ca H1047R mutation on breast cancer development and progression in different transgenic mouse models of breast cancer—specifically, MMTV-Neu and MMTV-Myc—which overexpress the neu and myc oncogenes, respectively. The experimental approach included animal genotyping, morphometric analysis of the mammary epithelial network in whole-mount preparations, and immunohistochemical detection of the Ki-67 cell proliferation marker. Through digital image analysis, we evaluated the morphometric characteristics of the mammary epithelium, the Ki-67 index in primary mammary tumors and lung metastatic lesions, as well as the metastatic burden based on the number and size of the metastatic lesions. The results showed differences between the MMTV-Neu and MMTV-Myc oncogenic backgrounds regarding mammary epithelial morphology and tumor proliferative activity. The loss of ARID1A in the MMTV-Neu background was associated with an increased Ki-67 index in primary mammary tumors, without a corresponding increase in metastatic lesions. In parallel, models with ARID1A loss showed enhanced development of the mammary epithelial network and an increased metastatic burden compared to the respective reference models. The WAP-Cre; Pik3caH1047R/MMTV-Neu model also showed enhanced development and increased density of the mammary epithelial network, as well as a trend toward an increase in the number and size of lung metastatic lesions, without a corresponding increase in the Ki-67 index. The findings of this study provide evidence that the loss of ARID1A enhances characteristics of mammary tumor development and metastatic progression, with effects that differ depending on the oncogenic background. In parallel, the activation of Pik3ca H1047R in the MMTV-Neu background appears to be associated with strong morphological changes in the mammary epithelium and an increased metastatic burden. Due to the limited number of samples, these results are considered preliminary and require confirmation in larger experimental series.