Vascular endothelial growth factor A (VEGF-A) mRNA expression levels decrease after menopause in normal breast tissue but not in breast cancer lesions

Abstract

SummaryWe hypothesized that the regulation of microvascular functions and angiogenesis in breast tissue, a well known target of ovarian steroid action, is dependent on the hormonal exposure of the breast. Relative expression levels of VEGF-A (vascular endothelial growth factor A), a putative key regulator of angiogenesis in breast cancer, were analysed in the tumour and the adjacent non-neoplastic breast tissue of 19 breast cancer patients by quantitative reverse transcriptase polymerase chain reaction. In non-neoplastic breast specimens the expression levels of all detected VEGF-A-isoforms (189, 165, 121) were significantly higher in premenopausal compared to post-menopausal women (P = 0.02) and were inversely correlated with the patient's age (P = 0.006). In contrast, in cancerous tissues menopausal status had no influence on VEGF-A-expression levels. Benign and malignant tissues exhibited a similar expression pattern of VEGF-A-isoforms relative to each other. Thus, the regulation of the vasculature in normal breast tissue, as opposed to breast cancer tissue, appears to be hormonally dependent. Endogenous and therapeutically used hormonal steroids might, therefore, cause clinically relevant changes of the angiogenic phenotype of the human breast.

Vascular remodelling during the normal and malignant life cycle of the mammary gland

“…Indeed, it has been shown that VEGF-A is expressed by some breast cancer cell lines and is regulated by oestrogens and progestins (Hyder et al, 1998;Nakamura et al, 1996). VEGF-A expression in humans is significantly higher in pre-menopausal as compared to post-menopausal women indicating that steroid hormones also regulate VEGF expression in vivo (Greb et al, 1999). In addition to endothelial growth factors such as VEGF-A, the mammary gland also produces a number of vasodilatory compounds including parathyroid hormone-related protein (see Durban and Wysolmerski, pages 163-170, this issue), prostacyclin, nitric oxide, and endothelin.…”

Endothelial Progenitor Cells Significantly Contribute to Vasculatures in Human and Mouse Breast Tumors

“…One of the main reasons for this limited efficacy is the propensity for malignant tumors to switch to production of other angiogenic molecules [44][45][46][47][48][49][50][51][52][53][54][55][56]. In the present study, we show that advanced stage breast tumors and mouse carcinomas expressed G-CSF and that inhibition of the cytokine in the 4T1 model prolonged the survival of the tumor-bearing mice.…”

“…Several studies show that VEGF-A, an angiogenic factor that is expressed in normal and transformed breast tissues [50,51], induces EPCs mobilization and differentiation into ECs [7,33]. The observation that VEGF inhibitors such as endostatin and bevacizumab suppress EPC recruitment and vascularization in mice [52] and patients with colorectal cancer [44,45] has strengthened the belief that VEGF plays a critical role in EPC generation and tumor vascularization.…”

“…Curiously, the G-CSF-expressing, metastatic human breast tumors were negative for VEGF-A (Supplemental Fig. 16A and 16B), a potent angiogenic stimulant that is expressed in normal mammary epithelial cells [50,51] and overexpressed in breast and other cancers [2-6, 44, 50-52].…”

Targets for regulating angiogenesis in the ageing endothelium

“…In fact, the decrease in VEGF has also been linked to the decline in oestrogen signalling in postmenopausal women [80] . Models of wound healing have shown that there is less induction of VEGF and basic FGF in response to injury in older animals [81,82] .…”