Progesterone facilitates chromosome instability (aneuploidy) in p53 null

Abstract

Mammary epithelial cells from p53 null mice have been shown recently to exhibit an increased risk for tumor development. Hormonal stimulation markedly increased tumor development in p53 null mammary cells. Here we demonstrate that mammary tumors arising in p53 null mammary cells are highly aneuploid, with greater than 70% of the tumor cells containing altered chromosome number and a mean chromosome number of 56. Normal mammary cells of p53 null genotype and aged less than 14 wk do not exhibit aneuploidy in primary cell culture. Significantly, the hormone progesterone, but not estrogen, increases the incidence of aneuploidy in morphologically normal p53 null mammary epithelial cells. Such cells exhibited 40% aneuploidy and a mean chromosome number of 54. The increase in aneuploidy measured in p53 null tumor cells or hormonally stimulated normal p53 null cells was not accompanied by centrosome amplification. These results suggest that normal levels of progesterone can facilitate chromosomal instability in the absence of the tumor suppressor gene, p53. The results support the emerging hypothesis based both on human epidemiological and animal model studies that progesterone markedly enhances mammary tumorigenesis.

Serial analysis of gene expression in normal p53 null mammary epithelium

“…By 7 weeks after transplantation, the mammary epithelial cells completely fill the mammary fat pad of the virgin hosts with normal duct. In the presence of hormone stimulation, both genotypes exhibit complete lobuloalveolar differentiation equivalent to late pregnancy (Goepfert et al, 2000). It was observed in this system that by 5 months posttransplantation the hormonally stimulated p53 null transplants start developing mammary adenocarcinomas rapidly reaching a 100% incidence in a few months; in contrast, no tumors are observed in the p53 wt counterparts (Jerry et al, 2000).…”

“…This study is unique as it focused on an in vivo model of preneoplastic phenotype and examined the transcriptome of morphologically 'normal' cells prior to any histopathological changes. In this model, the mammary epithelial transplants derived from both genotypes (p53 null and p53 wt ) develop identical gland structures with no detectable differences at the gross morphological or histological level (Goepfert et al, 2000;Jerry et al, 2000). By 7 weeks after transplantation, the mammary epithelial cells completely fill the mammary fat pad of the virgin hosts with normal duct.…”

Overexpression of Separase induces aneuploidy and mammary tumorigenesis

“…1 A). On days 5 and 15, chromosome numbers were measured by using conventional G banding techniques as described (5,11). For each preparation, 40-85 metaphases from exponentially growing cells were examined, and total chromosome numbers were counted by using QUIPS Pathvysion software (Applied Imaging) (see Fig.…”

The emerging role of p53 in stem cells

“…Accordingly, p53 À/À mice, at least in the murine genetic background C57/BL6, rarely develop mammary tumors [34,[36][37][38][39]. Nevertheless, several observations suggest that loss of p53 is involved in the etiopathology of both human and mouse mammary tumors: (i) mutations of p53 are found in many breast cancers and women affected by the Li-Fraumeni syndrome (an inherited predisposition to cancer development linked to germline mutations in the p53 gene) often develop breast tumors [38]; (ii) in the BALB/c background, approximately 75% of p53 À/À mice have microscopic lesions in the mammary gland (sarcomas, epithelial hyperplasia and alterations in stromal morphology) [40]; (iii) transplantation of the p53 À/À BALB/c epithelium into fat pads of WT syngeneic mice leads to the development of mammary carcinomas in 60-75% of mice [40,41]; (iv) in a conditional mammary tumor model, approximately 70% of mice that carry tissue-specific inactivation of p53 develop mammary carcinomas [42]; and (v) in ErbB2 transgenic mice, which develop mammary carcinomas with high penetrance and short latency, p53 impairment is responsible for the immortal behavior and the geometric expansion of mammary CSCs in vitro and for carcinoma growth in vivo [34].…”