Sex-steroid regulation of vascular endothelial growth factor in breast cancer

Abstract

Angiogenesis is a key event, which occurs in both normal and pathological expansion of tissues and provides the nourishment necessary for growth. The role of angiogenic growth factors in breast pathology is rapidly gaining recognition since scientists and clinicians realized that these factors could function as molecular targets event 550 209822 for controlling tumor expansion. Vascular endothelial growth factor (VEGF) is a key regulator of angiogenesis. Although significant advances have been made in understanding the sex-steroid-dependent regulation of this key factor, the role of VEGF in controlling breast tumors is not well understood. In this review, I discuss recent studies describing the role of the female sex steroids estrogens and progestins in the regulation of VEGF in breast cancer cells. Furthermore, I present a summary of recent studies from other biological systems (mainly focused on tumor biology) directed towards providing us with a better understanding of the regulation of classical VEGF and VEGF receptors. I propose that by extending such studies we will gain deeper insights into how we might combat the progression of breast cancer by controlling hormonedependent angiogenesis within tumor tissue. I believe that information gained from such studies will permit us to target angiogenic growth factors and their initiated signal transduction pathways in a more precise and selective manner, and thereby to control the formation of new blood vessels that fuel the rapid growth of breast tumors. Finally, it is my hope that the concepts discussed here will help elucidate molecular targets in the hormone-dependent angiogenesis pathway that will ultimately allow us to overcome anti-hormone resistance and to provide insights into how we might pursue the concept of chemoprevention by considering 'angioprevention' as the end point.

Apigenin Induces Apoptosis and Blocks Growth of Medroxyprogesterone Acetate-Dependent BT-474 Xenograft Tumors

“…This supports the hypothesis that progestins may promote the proliferation of latent breast tumor cells, which may contribute to the increased breast cancer risk associated with progestincontaining HRT [10,11,21,41]. Apigenin blocked MPAinduced proliferation, reducing levels of tumor cell proliferation to those observed in controls.…”

“…As a result, the use of combination HRT has become controversial and recent epidemiological studies link the decline in HRT to reduced incidence of ductal carcinoma in situ, particularly hormone-receptor-positive invasive breast cancer [7][8][9][10]. Due to the rapid onset of tumor growth in postmenopausal women undergoing combination HRT, we and others have suggested that the progestin component promotes the progression of latent tumor cells or stimulates proliferation of cancer stem cells [11,12].…”

“…A number of mechanisms have been proposed to explain progestin-stimulated breast cancer in post-menopausal women [11][12][13]. Several studies showed that progestins induce the expression of vascular endothelial growth factor (VEGF), a potent pro-angiogenic factor, in human and rodent breast cancer cells [11,14].…”

“…Several studies showed that progestins induce the expression of vascular endothelial growth factor (VEGF), a potent pro-angiogenic factor, in human and rodent breast cancer cells [11,14]. Another study showed that progestins activate several genes that promote cell transformation, increase cell motility, and increase the rate of cancer metastasis [15].…”

In vivo MRI and histopathological assessment of tumor microenvironment in luminal‐like and basal‐like breast cancer xenografts

“…VEGF is also known to augment capillary permeability (33). Although there have been several reports concerning estrogen regulation of VEGF in breast cancer, the findings are still controversial and the underlying mechanism remains unclear (35). In this study, western blotting analysis of biopsies from the hormone receptor-positive luminal-like tumors harvested 3 and 10 days after estradiol withdrawal showed more phosphorylation of VEGFR2 compared to controls.…”