Ovarian hyperstimulation induces centrosome amplification and aneuploid mammary tumors independently of alterations in p53 in a transgenic mouse model of breast cancer

Abstract

Aneuploidy and genomic instability are common features of human cancers, including breast cancer; however, mechanisms by which such abnormalities develop are not understood. The exquisite dependence of the mammary gland on hormones for growth and development as well as hormonal contributions to breast cancer risk and progression suggest that tumorigenic mechanisms in the breast should be considered in the context of hormonal stimulation. We used transgenic mice that overexpress luteinizing hormone with subsequent ovarian hyperstimulation as a model to identify mechanisms involved in hormone-induced mammary cancer. Tumor pathology in these mice is highly variable, suggesting individual tumors undergo distinct initiating or promoting events. Supporting this notion, hormone-induced tumors display considerable chromosomal instability and aneuploidy, despite the presence of functional p53. The presence of extensive centrosome amplification in tumors and hyperplastic glands prior to tumor formation suggests that alterations in the ovarian hormonal milieu dysregulate the centrosome cycle in mammary epithelial cells, leading to aneuploidy and cancer.

Biomarker-guided sequential targeted therapies to overcome therapy resistance in rapidly evolving highly aggressive mammary tumors

“…Importantly, the mouse model that we used (PTEN −/− /NIC) reflects the intratumoral heterogeneity of breast cancer as PTEN loss is highly heterogeneous (determined by IHC), indicating that some parts of the tumor may be primarily driven by ErbB2/neu while others are driven by PTEN loss as well (Supplementary information, Figure S7). Similar heterogeneity has also been reported in other GEM models [34,35]. Additionally, our experimental approach of testing drugs in a time-efficient and robust manner using transplantation in immune-competent mice could be utilized for setting up synchronous mouse co-clinical trials to www.cell-research.com | Cell Research Ozgur Sahin et al 557…”

Mps1 as a link between centrosomes and genomic instability

“…At least in some breast (Lingle et al 2002) and prostate (Pihan et al 2001; Pihan et al 2003) tumors extra centrosomes appear prior to aneuploidy, suggesting that in such tumors the extra centrosomes arose via defects in centrosome duplication. In addition, centrosome defects precede tumor formation in a mouse model of hormone-induced breast tumorigenesis (Milliken et al 2008), and their presence strongly correlates with aneuploidy in higher grade tumors (Lingle et al 2002; Lingle et al 1998). Together these observations suggest that errors in centrosome duplication might promote the genetic instability that is thought to be important in tumorigenesis (Ellsworth et al 2004a; Ellsworth et al 2004b; Lengauer et al 1998; Tsikitis and Chung 2006).…”

Overexpression of WDR62 is associated with centrosome amplification in human ovarian cancer

“…Immunofluorescences staining of centrosomes were performed as previously described [17]. Briefly, treated cells were rinsed with ice-cold phosphate- buffered saline (PBS, pH 7.4) and were fixed with 3% paraformaldehyde.…”

“…Centrosome structures and count was estimated according to the definition as previously described [17,20]. Briefly, endogenous peroxidase was quenched with 3% H 2 O 2 , slides were blocked with 5% normal goat serum for 15 min, followed by incubation with mouse anti-human g-tubulin antibody to identify centrosomes (200 μg/mL; Santa Cruz, Inc.) for 1h at room temperature.…”