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VEGF(A protein that promotes angiogenesis and is known to be a prognostic factor in several types of tumour) in breast cancer

Elevated levels of VEGF correlate with poor prognosis in patients with breast cancer,1–5 and research continues to provide insights into the complex and critical role played by VEGF in this disease.

VEGF is recognised as an important mediator of angiogenesis(The growth of new blood vessels from pre-existing vessels) across a range of solid tumour(An abnormal growth of cells, forming a mass of tissue) types. In breast cancer, VEGF is the only known pro-angiogenic factor(A substance that causes the growth of new blood vessels) expressed throughout the entire life cycle of a malignancy(The tendency of a medical condition, especially tumours, to become progressively worse and to potentially result in death).6 VEGF appears to play a critical role, enhancing tumour growth and metastasis(The spread of a disease from one organ or part to another non-adjacent organ or part), across many forms of the disease, including invasive(Cancer that has spread into nearby healthy tissue; also described as infiltrating)/non-invasive(Confined to the original location; unable to spread to nearby tissues), lymph(A transparent, usually slightly yellow, often opalescent liquid found within the lymphatic vessels, and collected from tissues in all parts of the body and returned to the blood via the lymphatic system) node-negative/lymph node-positive, inflammatory breast cancer(An especially aggressive type of breast cancer frequently presented with symptoms resembling an inflammation and can occur in women of any age (and extremely rarely, in men)) and mBC.1–5,7

The negative impact of high VEGF expression on patient prognosis is likely to be mediated, in part, through VEGF’s pro-angiogenic properties. In primary breast tumours, high levels of VEGF correlate with elevated levels of microvascular density(A widely applied morphologic measure of vascularisation),8,9 which are in turn associated with increased incidence of metastatic(Pertaining to the spread of a disease, usually cancer, from one organ or part to another non-adjacent organ or part) disease.10 However, some investigators have hypothesised that the role of VEGF in breast cancer is not limited to angiogenesis .

  • The presence of both VEGF and VEGFRs may allow breast cancer cells to promote their own growth and avoid apoptosis(The process of programmed cell death that may occur in multicellular organisms) through an autocrine signalling(A form of signalling in which a cell secretes a hormone or chemical messenger (called the autocrine agent) that binds to autocrine receptors on the same cell, leading to changes in the cell) loop.11 This autocrine signalling may also contribute to cancer cell migration(The orchestrated movement of cells in particular directions to specific locations - a central process in the development and maintenance of multicellular organisms) and progression(A carcinogenic process whereby genetically altered cells undergo a second (non-genetic) cell expansion resulting in uncontrollable growth).11
  • VEGF stimulates differentiation of monocytes into osteoclast-like cells, suggesting that VEGF may be involved in breast cancer metastasis to bone.12
  • A relationship between increased VEGF expression and poor response to conventional systemic therapies, specifically tamoxifen or chemotherapy, has been observed.4 In patients with advanced breast cancer who receive these treatments, intermediate and high VEGF levels correlate with shorter PFS(The time from trial entry to disease progression or death from any cause) and post-relapse(Occurs when a person is affected again by a condition that affected him in the past (e.g. a cancer that may recur)) survival.4

In addition, VEGF is known to interact closely with other important breast cancer tumour markers(Substances found in the blood, urine, or body tissues that can be elevated in cancer) such as ERs, HER-2/neu and BRCA-1(BReast CAncer 1 is a tumour suppressor gene expressed in the cells of breast and other tissue, where it helps repair damaged DNA, or destroy cells if DNA cannot be repaired).

  • In breast cancer, elevated VEGF expression correlates with high levels of oestrogen and also with ER-negative tumour status.13,14 VEGF would appear to control angiogenesis and oestrogen-independent tumour growth in oestrogen-dependent breast cancers,13 and would appear to predict OS(The time from trial entry to death from any cause) in patients receiving adjuvant anti-oestrogen therapy for ER-positive breast cancers .2
  • HER-2/neu-overexpressing tumours reportedly express significantly more VEGF than HER-2/neu-non-overexpressing tumours, and the poorest patient outcomes are seen in tumours with high levels of HER-2/neu and VEGF expression.1
  • Normal BRCA-1 protein is thought to suppress VEGF expression and secretion. In contrast mutated BRCA-1 protein would appear to lack this capability, and dysregulation of VEGF function may partially explain the tumourigenic potential of mutated BRCA-1.7

Large prospective studies are essential to better define the relationships between VEGF, angiogenesis and prognosis in breast cancer.

Reference

  1. Konecny GE, Meng YG, Untch M, et al. Clin Cancer Res 2004;10:1706–16.
  2. Linderholm B, Grankvist K, Wilking N, et al. J Clin Oncol 2000;18:1423–31.
  3. Gasparini G, Toi M, Gion M, et al. J Natl Cancer Inst 1997;89:139–47.
  4. Foekens JA, Peters HA, Grebenchtchikov N, et al. Cancer Res 2001;61:5407–14.
  5. Gasparini G, Toi M, Miceli R, et al. Cancer J Sci Am 1999;5:101–11.
  6. Folkman J. In: DeVita VT, Hellman SMD, Rosenberg SA, editors. Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia: Lippincott Williams & Wilkins, 2005. p. 2865–82.
  7. Kawai H, Li H, Chun P, et al. Oncogene 2002;21:7730–9.
  8. Toi M, Inada K, Suzuki H, Tominaga T. Breast Cancer Res Treat 1995;36:193–204.
  9. Guidi AJ, Schnitt SJ, Fischer L, et al. Cancer 1997;80:1945–53.
  10. Weidner N, Semple JP, Welch WR, Folkman J. N Engl J Med 1991;324:1–8.
  11. Mercurio AM, Lipscomb EA, Bachelder RE. J Mammary Gland Biol Neoplasia 2005;10:283–90.
  12. Aldridge SE, Lennard TW, Williams JR, Birch MA. Br J Cancer 2005;92:1531–7.
  13. Buteau-Lozano H, Ancelin M, Lardeux B, et al. Cancer Res 2002;62:4977–84.
  14. Fuckar D, Dekanic A, Stifter S, et al. Int J Surg Pathol 2006;14:49–55.

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