Cyclin A1 modulates the expression of vascular endothelial growth factor and promotes hormone-dependent growth and angiogenesis in breast cancer

PLOS ONE. 2013 Aug 8; 8(8):e72210.

#Azharuddin Sajid Syed Khaja1, #Nishtman Dizeyi2, Pradeep Kumar Kopparapu3, Lola Anagnostaki4, Pirkko Härkönen5, and Jenny Liao Persson3*

1Center for Molecular Pathology, 2Division of Urological Research, Department of Clinical Sciences; 3Division of Experimental Cancer Research, Department of Laboratory Medicine;  4Department of Clinical Pathology, Lund University, Malmö, Sweden, 20502; 5Institute of Biomedicine, University of Turku, Finland.

PMID. 23991063

 

Abstract

Alterations in endocrine and in vascular endothelial growth factor (VEGF)-regulated pathways are implicated in angiogenesis and progression of breast cancer. Inhibition of the elevated levels of either of these pathways is associated with clinical benefits. However, it remains largely unknown how the endocrine and VEGF pathways are coordinated and altered during breast cancer progression and metastasis. In the present study, we show that the A-type cyclin, cyclin A1 with a known role in tumorigenesis in leukemia and prostate cancer, is highly expressed in primary and metastatic tumor tissues from patients with breast cancer,  which is in contrast to the barely detectable level of cyclin A1 transcript in normal human breast tissues. We observe a statistically significant correlation between the expression of cyclin A1 and VEGF in breast cancer specimens from two patient cohorts (p<0.01). We further demonstrate that cyclin A1 overexpression increases the invasiveness of MCF-7 and MDA-MB-231 breast cancer cells. Cyclin A1-induced invasive phenotype in MCF-7 cells is associated with its ability to increase VEGF expression alone or in combination with 17-β-estradiol (E2). In addition, overexpression of cyclin A1 also enhances the expression of estrogen receptor ER-a and cyclin A1 is able to physically interact with ER-a in MCF-7 cells. In mouse tumor xenograft models, cyclin A1 overexpression accelerates the growth of MCF-7 breast tumors, which is accompanied with a higher degree of angiogenesis and increased expression of VEGF, VEGFR1 and ER-a.  Our findings unravelled a novel role for cyclin A1 in breast cancer growth and progression, and suggest that multiple cellular pathways such as cell cycle, angiogenesis and estrogen-mediated pathways are coordinated events during breast cancer progression.

PMID: 23991063

Supplement:

At least 70% of breast cancers are classified as ER-αpositive breast cancers, as the cancer cells express an elevated level of the nuclear receptor ER-α. As ER-α mediates estrogen effects and promotes growth and survival of breast cancer cells, thus, ER-α is the main target for anti-estrogen therapies [1].  Anti-estrogen therapy achieves its effect by interfering with ER-α action [2]. The anti-estrogen therapy is used to inhibit tumor cell proliferation and survival, which can in part be achieved by inhibiting the expression and activities of cell cycle regulators [2]. However, it remains poorly understood whether cell cycle pathways are functionally linked to or overlap with both estrogenic and vascular endothelial growth factor VEGF pathways. In addition, a large percentage of treated patients will experience disease recurrence, but the recurred tumors often do not respond to therapy [2]. VEGF is regulated by estrogen through ER-α in breast and uterine cells[3-6].VEGF- and VEGF receptor-mediated autocrine and paracrine signalling contribute to increased proliferation and survival of breast tumor cells [7-9]. Thus, better understanding of the cellular mechanisms underlying the functional relationship between ER-α and VEGF is important to designing novel therapies to co-inhibit endocrine and angiogenesis pathways for treatment of invasive breast cancer. Cell cycle regulatory pathway plays an important role in estrogen-dependent and independent growth of breast cancer cells [10].

In this study, we have revealed the molecular basis of the cellular and molecular network that cooperatively controls the breast cancer progression and invasion. Our present study provided novel information of the relationship between cell cycle regulatory pathways and pathways that are involved in VEGF and estrogen-dependent and independent mechanisms during breast cancer progression (Figure 1). We discovered that cyclin A1 was expressed at a high level in breast cancer. We showed that the majority of primary and metastatic breast cancer specimens had elevated levels of cyclin A1 and VEGF. We showed that cyclin A1 expression significantly correlated with VEGF expression in tumors from breast cancer patients. To our knowledge, the current investigation is the first study that reports cyclin A1 expression in large clinical materials including primary cancer and metastatic lesions from patients with breast cancer. Cyclin A1 overexpression increased the expression of ER-α in MCF-7 and T47D cells that contain functional ER-α. Thus, we for the first time identified a functional link between cyclin A1 and ER-α. Increased VEGF expression has previously been shown to impair the response to tamoxifen which is used for clinical treatment of ER-α positive breast cancer [11]. Our finding that cyclin A1 is involved in the modulation of both ER-α and VEGF pathways provides novel information for better understanding of the treatment response of breast cancer in the clinical settings.

Jenny Persson

Figure 1. Elevated cyclin A1 leads to the increased expression of ER-α and VEGF in breast cancer cells in the presence of estrogen. In addition, the presence of a high level of estrogen promotes VEGF expression through  ER-α.

 

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