Estrogen mediates Aurora-A overexpression, centrosome amplification, chromosomal instability, and breast cancer in female ACI rats

Abstract

Estrogens play a crucial role in the causation and development of sporadic human breast cancer (BC). Chromosomal instability (CIN) is a defining trait of early human ductal carcinoma in situ (DCIS) and is believed to precipitate breast oncogenesis. We reported earlier that 100% of female ACI (August͞Copenhagen͞Irish) rats treated with essentially physiological serum levels of 17␤-estradiol lead to mammary gland tumors with histopathologic, cellular, molecular, and ploidy changes remarkably similar to those seen in human DCIS and invasive sporadic ductal BC. Aurora-A (Aur-A), a centrosome kinase, and centrosome amplification have been implicated in the origin of aneuploidy via CIN. After 4 mo of estradiol treatment, levels of Aur-A and centrosomal proteins, ␥-tubulin and centrin, rose significantly in female ACI rat mammary glands and remained elevated in mammary tumors at 5-6 mo of estrogen treatment. Centrosome amplification was initially detected at 3 mo of treatment in focal dysplasias, before DCIS. At 5-6 mo, 90% of the mammary tumor centrosomes were amplified. Comparative genomic hybridization revealed nonrandom amplified chromosome regions in seven chromosomes with a frequency of 55-82% in 11 primary tumors each from individual rats. Thus, we report that estrogen is causally linked via estrogen receptor ␣ to Aur-A overexpression, centrosome amplification, CIN, and aneuploidy leading to BC in susceptible mammary gland cells. More than 90% of all human breast cancer (BC) cases are sporadic (1). Numerous epidemiological and animal studies show that both endogenous and exogenously ingested estrogens (Es) play a central, if not paramount, role in the causation and development of human sporadic BC (2-6). Recent epidemiological studies show only a minimal rise in BC risk in postmenopausal women taking E replacement therapy over varying periods of use (7-9). In premenopausal women, however, all of the well established risk factors clearly implicate Es in the causation of BC (2-6). In this latter group, 17␤-estradiol (E 2 ) concentrations, all in the low picogram range, within narrow limits of serum and breast tissue levels (10-13), are sufficient to increase sporadic BC risk. Therefore, it is essential to gain a better understanding of how Es, at these physiological concentrations, elicit their oncogenic effects in susceptible target tissues.Chromosomal instability (CIN) and aneuploidy are defining traits of early human BC ductal carcinoma in situ (DCIS) and primary invasive ductal BCs. These distinguishing characteristics of human BC have been seen in 55-78% of the DCISs and in 85-92% of invasive ductal BCs (14-17). Aneuploidy has been a reliable biomarker for BC for many decades. However, it has not been realized until now that it provides an important clue to the causation of sporadic human BC and the involvement of Es in its etiology.Overexpression of a centrosome kinase, Aurora-A (Aur-A), centrosome amplification, and CIN invariably occur together (18,19). Centrosome amplification, found in human BC, may play...

Impaired p53 function leads to centrosome amplification, acquired ERα phenotypic heterogeneity and distant metastases in breast cancer MCF-7 xenografts

“…Chromosomal instability and consequent aneuploidy are the hallmarks of breast cancer and represent a mechanism for the evolution of phenotypic diversity in cancer cell populations (Lengauer et al, 1998;Lingle et al, 2002;Kawamura et al, 2004;Fukasawa, 2005;Suizu et al, 2006). Importantly, earlier we established a mechanistic link between estrogen and the development of centrosome amplification and chromosomal instability in the ACI rat model for mammary tumorigenesis (Li et al, 2004).…”

Downregulation of Aurora-A overrides estrogen-mediated growth and chemoresistance in breast cancer cells

“…Higher levels of Aurora-A was observed in E 2 -treated cells in an ER-dependent manner Long-term treatment of estrogen to female rats resulted in centrosome amplification, mammary tumorigenesis, and upregulation of c-myc and Aurora-A (Li et al 2004). It has been postulated that Aurora-A might be responsible for the phenotypes associated with estrogen-induced tumorigenesis in vivo.…”

“…The three proposed mechanisms responsible for the carcinogenicity of estrogens involve i) the receptormediated hormonal response; ii) cytochrome P450-mediated metabolic activation that leads to genotoxic effects, and iii) induction of aneuploidy by estrogen . Recently, it has been shown that long-term treatment of estrogen in rats resulted in mammary gland tumorigenesis with characteristics of DCIS and was accompanied by the upregulation of oncogenes such as myc and Aurora-A (Li et al 2004). Similarly, in an estrogen-induced Syrian hamster kidney tumor model, centrosome amplification and overexpression of Aurora-A and Aurora-B was observed in a receptor-dependent fashion (Hontze et al 2007).…”

“…Female August/ Copenhagen/Irish (ACI) rats treated with physiological levels of 17b-estradiol (E 2 ) developed mammary gland tumors with characteristics similar to those in ductal carcinoma in situ (DCIS) and invasive sporadic ductal breast cancer (Li et al 2002). Prolonged treatment of estrogen in these rats for 4 months caused centrosomal abnormalities, aneuploidy generated by random and non-random chromosome changes and upregulation of key molecules such as myc and Aurora-A (Li et al 2004). Similarities in the phenotypes led them to propose that upregulation of myc and Aurora-A could be responsible for the phenotypic changes associated with the estrogen-induced mammary gland tumorigenesis.…”

Exposure to estrogen and ionizing radiation causes epigenetic dysregulation, activation of mitogen-activated protein kinase pathways, and genome instability in the mammary gland of ACI rats

“…60,61 Indeed, our results that demonstrated a substantial increase in histone H3S10 phosphorylation correspond to previous findings of overexpression of Aurora-A and chromosomal instability during breast carcinogenesis in ACI rats. 62 Furthermore, previous studies have demonstrated that genotoxic DNA-damaging agents can induce phosphorylation of H3S10 through the activation of the MAPK pathway. 43 There are four distinct MAPK cascades that include the extracellular signal-regulated kinase (p42/44 ERK)/MAPK 1 and 2 pathway (p42/44 MAPK), the p38 pathway, the c-jun N-terminal kinase (JNK)/stress-activated protein kinase (SAPK) pathway, and the mitogen-activated protein kinase/ERK5 pathway.…”