{'fraction_non_alphanumeric': 0.030561122244488977, 'fraction_numerical': 0.01903807615230461, 'mean_word_length': 5.339682539682539, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Repression of p63 and induction of EMT by mutant Ras in mammary epithelial cells

Significance The oncogenes Harvey Rat Sarcoma Virus GTPase (H-RAS) and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) are well known for altering cell growth and morphology. We show here that they are also able to modify the differentiation state of mammary epithelial cells by inducing an epithelial-to-mesenchymal transition (EMT). This transition leads to greater invasiveness, a hallmark of the progression of tumors toward metastasis. Expression of p63, a protein required for the development of mammary epithelial cells, is strongly repressed by these oncogenes. In turn, loss of p63, which occurs at the transcriptional level, causes a shift in microRNAs and transcription factors that control EMT. Targeting specific genes within this Ras-to-EMT axis may be useful as a therapy to block breast cancer progression. The p53-related transcription factor p63 is required for maintenance of epithelial cell differentiation. We found that activated forms of the Harvey Rat Sarcoma Virus GTPase (H-RAS) and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) oncogenes strongly repress expression of ∆Np63α, the predominant p63 isoform in basal mammary epithelial cells. This regulation occurs at the transcriptional level, and a short region of the ∆Np63 promoter is sufficient for repression induced by H-RasV12. The suppression of ∆Np63α expression by these oncogenes concomitantly leads to an epithelial-to-mesenchymal transition (EMT). In addition, the depletion of ∆Np63α alone is sufficient to induce EMT. Both H-RasV12 expression and ∆Np63α depletion induce individual cell invasion in a 3D collagen gel in vitro system, thereby demonstrating how Ras can drive the mammary epithelial cell state toward greater invasive ability. Together, these results suggest a pathway by which RAS and PIK3CA oncogenes induce EMT through regulation of ∆Np63α.