Cyclin A1 Modulates the Expression of Vascular Endothelial Growth Factor and Promotes Hormone-Dependent Growth and Angiogenesis of Breast Cancer

Abstract

Alterations in cellular pathways related to both endocrine and vascular endothelial growth factors (VEGF) may contribute to breast cancer progression. Inhibition of the elevated levels of these pathways is associated with clinical benefits. However, molecular mechanisms by which endocrine-related pathways and VEGF signalling cooperatively promote breast cancer progression remain poorly understood. In the present study, we show that the A-type cyclin, cyclin A1, known for its important role in the initiation of leukemia and prostate cancer metastasis, is highly expressed in primary breast cancer specimens and metastatic lesions, in contrasting to its barely detectable expression in normal human breast tissues. There is a statistically significant correlation between cyclin A1 and VEGF expression in breast cancer specimens from two patient cohorts (p<0.01). Induction of cyclin A1 overexpression in breast cancer cell line MCF-7 results in an enhanced invasiveness and a concomitant increase in VEGF expression. In addition, there is a formation of protein–protein complexes between cyclin A1 and estrogen receptor ER-α cyclin A1 overexpression increases ER-α expression in MCF-7 and T47D cells. In mouse tumor xenograft models in which mice were implanted with MCF-7 cells that overexpressed cyclin A1 or control vector, cyclin A1 overexpression results in an increase in tumor growth and angiogenesis, which is coincident with an enhanced expression of VEGF, VEGFR1 and ER-α Our findings unravel a novel role for cyclin A1 in growth and progression of breast cancer, and suggest that multiple cellular pathways, including cell cycle regulators, angiogenesis and estrogen receptor signalling, may cooperatively contribute to breast cancer progression.

Polydatin Induces Apoptosis and Inhibits Growth of Acute Monocytic Leukemia Cells

“…During normal phase progression and at key cell-cycle transition phases, specific cyclins are activated. Aberrant activation of cyclins can lead to cancer formation [21][22][23]. In the current study, increased ratio of S phase cells and decreased ratio of G0/G1 phase cells were detected, meanwhile decreased expression of cyclin D1 and increased expression of cyclin A were observed in THP-1 cells after treated with PD.…”

Cyclin A1 and P450 Aromatase Promote Metastatic Homing and Growth of Stem-like Prostate Cancer Cells in the Bone Marrow

“…In metastatic PC3 cells, cyclin A1 is functionally associated with VEGF and MMP2/MMP9 (47). Recently, we reported that cyclin A1 interacts with ERa to promote breast cancer progression in xenograft mouse models (48). Cyclin A1 function is required for hematopoietic stem and progenitor cells (HSPC) to home to their bone marrow niches (49).…”

A comparative study of hepatitis B virus X protein mutants K130M, V131I and KV130/131MI to investigate their roles in fibrosis, cirrhosis and hepatocellular carcinoma

“…Enhanced expression of cyclinA1 is also associated with aggressive, metastatic and invasive attributes of human cancer cells . c‐myb overexpression is associated with metastasis of HCC and other cancers .…”

“…Enhanced expression of cyclinA1 is also associated with aggressive, metastatic and invasive attributes of human cancer cells. [60][61][62] c-myb overexpression is associated with metastasis of HCC and other cancers. 63,64 So, KV130/131MI may partly contribute in HCC metastasis via inducing expression of p27, cyclinA1 and c-myb (Figure 4).…”