Overexpression of Cyclin D1 alone, however, does not lead to cancer; instead, a concurrent inactivation or loss of p53/21 or p16/Rb or, alternatively, activation of a second oncogene, appears to take place prior to cell transformation, with both an intact p53 and Retinoblastoma pathways essential for maintaining this senescent cell arrest of tetraploid cells (Hosokawa et al., 2001; Montalto & De Amicis, 2020; Panopoulos et al., 2014; Serrano et al., 1997; Zhu et al., 1998). Here, RB1 is linked to cancer.