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

"Angiogenesis(The growth of new blood vessels from pre-existing vessels), the process of new blood vessel formation, plays a central role in both local tumour(An abnormal growth of cells, forming a mass of tissue) growth and distant metastasis(The spread of a disease from one organ or part to another non-adjacent organ or part) in breast cancer"

Schneider, et al. J Clin Oncol 20051

Breast cancer is one of the tumour types in which VEGF has been implicated as a key mediator of angiogenesis. It has been shown that

  • VEGF is expressed in a variety of breast cancer types.2–5
  • VEGF is involved throughout the breast tumour life cycle.6
  • VEGF expression is related to other breast cancer tumour markers(Substances found in the blood, urine, or body tissues that can be elevated in cancer).7–10
  • VEGF expression correlates with poor prognosis in breast cancer.3,4,11

Although scientists and clinicians have learned much about the role of VEGF and angiogenesis in breast cancer, many questions remain unanswered and research on this exciting topic remains robust.

Evidence of VEGF expression in breast cancer

VEGF: important across breast cancer tumour types

It has been shown that VEGF and angiogenesis are important to tumour growth and metastasis across a range of solid tumour types. This appears to be the case in many forms of breast cancer, including invasive(Cancer that has spread into nearby healthy tissue; also described as infiltrating)/noninvasive, 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.2–5,10,11

In one study, Yoshiji and colleagues found that VEGF expression was markedly upregulated compared with surrounding normal tissue in each of the 18 human breast tissue samples evaluated.12 In a separate study assessing the role of VEGF in breast cancer, Brown and researchers observed VEGF to be expressed at high levels in ductal carcinoma(The medical term for a malignant tumour consisting of transformed epithelial cells, but include transformed cells of unknown cell lineage or origin) (comedo-type, invasive and metastatic(Pertaining to the spread of a disease, usually cancer, from one organ or part to another non-adjacent organ or part)) but not in infiltrating lobular carcinoma.13 A third study, reported in 2006 by Jacobs and colleagues, showed that an increased risk of invasive breast cancer was correlated with two VEGF gene polymorphisms, VEGF-2578C and VEGF-1154G. These polymorphisms are both hypothesised to increase expression of VEGF.14

 VEGF and angiogenesis in inflammatory breast cancer

Intense angiogenic activity has been observed in inflammatory breast cancer. In an attempt to characterise the angiogenic phenotype(The visible characteristics of an organism that are produced by the interaction of the organism’s genes and the environment) of this disease, Van der Auwera et al. measured mRNA(A molecule of RNA encoding a chemical 'blueprint' for a protein product) expression of tumour angiogenesis and lymphangiogenesis(The formation of lymphatic vessels from pre-existing lymphatic vessels, in a method believed to be similar to blood vessel development or angiogenesis) factors in patients with both inflammatory (n=16) and noninflammatory (n=20) breast cancer. Although both forms of the disease exhibited high levels of angiogenic activity, inflammatory breast cancer had significantly higher mRNA expression of angiogenic and lymphangiogenic genes, including those encoding for VEGF-C and VEGF-D. These observations may help clarify why inflammatory breast cancer has high metastatic potential via haematogenous and lymphatic routes.15

VEGF: a critical pro-angiogenic factor in breast cancer

In a study by Relf et al. expression of VEGF significantly correlated with an increased risk of relapse(Occurs when a person is affected again by a condition that affected him in the past (e.g. a cancer that may recur)). Of the six angiogenic factors studied by the investigators, only VEGF showed a significant correlation with relapse.16

In a series of elegant experiments, Relf and colleagues measured the mRNA levels of several angiogenic factors in 64 primary breast tumour samples and investigated relationships between expression levels and tumour growth and progression(A carcinogenic process whereby genetically altered cells undergo a second (non-genetic) cell expansion resulting in uncontrollable growth). The factors included VEGF, TGF-β1(One of several proteins secreted by transformed cells that can stimulate the growth of normal cells. TGF-β1 initiates a signalling pathway that suppresses the early development of cancer cells), pleiotrophin(A protein that in humans is encoded by the PTN gene. It is expressed by several tumour cells and is thought to be involved in tumour angiogenesis), and bFGF(Mitogenic growth factor that is widely utilised during wound-healing, growth and development) and PD-ECGF(A substance contained in the alpha granules of blood platelets whose action contributes to the growth of endothelial cells in blood vessel walls). Overall, they showed that VEGF is one of the most important mediators of tumour angiogenesis in human breast cancer tissue and that elevated VEGF mRNA levels correlated with poor survival. Importantly, Relf et al. also showed that, of all the angiogenic factors studied, VEGF was the only factor linked to poor relapse-free survival(The length of time after treatment during which the disease not recur in an individual patient or study population).16

VEGF: significant throughout breast malignancy development

While many pro-angiogenic factors have been identified in breast cancer, VEGF appears to be the only known factor expressed throughout the entire life cycle of a breast malignancy.6 The clinical significance of this finding is unknown.

VEGF and MVD

Several reports have confirmed that VEGF expression correlates with increased MVD in breast cancer. In a study published in Breast Cancer Research and Treatment, Toi and colleagues demonstrated a close correlation between VEGF expression and MVD in breast tumour biopsies. Their postoperative tissue analysis of 328 primary breast cancer samples showed a positive relationship between the rate of VEGF expression and MVD.17

Relationship between VEGF expression and MVD counts18

  VEGF expression
  Strong Low level p value
Median microvessel      
Count (± SD)
 100±30.6 71±48.6
 –
Range 37–147 33–229 –
Number (n) 22 24
 0.04
‘Strong’ VEGF expression, defined as cell clusters (three or more cells) showing 10 or more autoradiographic grains per cell, was observed in 22 cases (48%). ‘Low-level’ VEGF expression, defined as lesions showing fewer than 10 grains per cell, was observed in 24 cases (52%).18

Likewise, in a separate analysis of 46 DCIS breast tumour biopsies, Guidi and colleagues found a statistically significant(Pertaining to an event that is unlikely to have occurred by chance) correlation between VEGF mRNA expression and the degree of angiogenesis.18 Other research has also suggested that microvascular density(A widely applied morphologic measure of vascularisation) in breast cancer might play a role in prognosis.

Does the pattern of angiogenesis change as malignancies develop?

Researchers often evaluate malignancies over several phases of their life cycle to determine the pathological stepwise progression from early to metastatic disease. Using this methodology, Guidi and colleagues hypothesised that the pattern of angiogenesis would differ from early- to late-stage breast malignancies. In an assessment of samples from 110 breast cancer patients (47 with primary tumours and 91 with metastatic axillary lymph nodes(Small, ball-shaped organ of the immune system, located under the armpit (axilla))), the presence of microvascular ‘hot spots’ in lymph node(Bodies of lymphoid tissue located along the course of lymphatic vessels; involved in the filtration of lymph) metastases (but not in primary tumours) was a significant predictor of disease-free survival (p=0.006) and OS(The time from trial entry to death from any cause) (p=0.004).19 This suggests that metastatic tumours may have different angiogenic properties and behaviour than primary tumours.19,20

VEGF and other common tumour markers in breast cancer

A variety of tumour markers are correlated with breast cancer. These include 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). Recent research has correlated several breast cancer tumour markers with VEGF expression.

For more information on the relationship of VEGF and other tumour markers in breast cancer, see below.

Common tumour and markers and VEGF in breast cancer

Tumour marker Findings Studies
Oestrogen/ER VEGF expression may be regulated by oestrogen
VEGF levels have been associated with response to anti-oestrogen therapy
VEGF has been correlated with ER-negative status
 Buteau-Lozano, et al.
Cancer Res 20027
Linderholm, et al. J Clin Oncol 20005
Fuckar, et al. Int J Surg
Pathol 20068
HER-2
 VEGF correlates with HER-2/neu positivity Konecny, et al. Clin
Cancer Res 20044
Fuckar, et al. Int J Surg
Pathol 20068
BRCA-1 VEGF expression is controlled by an interaction of BRCA-1 and the ER Kawai, et al. Oncogene
200210

VEGF, oestrogen and ER(A hormone receptor specific to oestrogen that is found at high levels in some breast cancers; binding of oestrogen to ER can cause accelerated growth of these tumours) status in breast cancer

Results from a number of studies indicate that expression of growth factors, such as VEGF, can be regulated by hormones via direct (autocrine) and indirect (paracrine) mechanisms. One example is the relationship between oestrogen and VEGF expression in breast cancer. Buteau-Lozano and colleagues confirmed, in preclinical models, that oestrogen modulates VEGF expression at the gene transcriptional level in breast cancer cells, suggesting a complex relationship between oestrogen and VEGF expression. Additional research suggests that VEGF expression in oestrogen-dependent breast cancers contributes to both angiogenesis and oestrogen-independent growth.7 Furthermore, VEGF levels have been shown to predict OS in patients receiving adjuvant anti-oestrogen therapy for ER-positive breast cancer.5

The work of Buteau-Lozano and colleagues showed that the hormone(A type of chemical substance secreted within the body that travels within the blood to another location, where it has a regulatory effect) oestrogen increased VEGF production. However, the receptor(Proteins located on the cell surface. When a specific molecule called a ligand binds to a receptor, signalling pathways are activated) for oestrogen may have a different relationship with VEGF, as shown in a 2006 study. Fuckar and colleagues reported the results of a study of 233 breast cancer specimens investigating the relationship between VEGF, hormone receptor status and other variables. In this study, VEGF expression significantly correlated with ER-negative status. Note that prognosis for patients with ER-negative breast cancer is generally poorer than ER-positive breast cancer.8

VEGF and HER-2 in breast cancer

Activation of the HER-2/neu proto-oncogene, which is amplified and overexpressed in 20–25% of human breast cancers, has also been correlated with VEGF upregulation. In an analysis of tumours from 611 breast cancer patients (114 of whom were HER-2/neu positive), on average, HER-2/neu-overexpressing tumours were found to express significantly more VEGF than HER-2/neu-nonoverexpressing tumours. In this study, the poorest outcomes were seen in tumours with both HER-2/neu overexpression and VEGF expression, a statistically significant relationship. The positive correlation of HER-2/neu and VEGF expression may contribute to the aggressive phenotype of HER-2/neu-overexpressing tumours.4 A more recent study by Fuckar and colleagues showed a significant positive correlation between VEGF expression and HER-2/neu overexpression, but only in tumours from postmenopausal patients.8

VEGF and BRCA-1 in breast cancer

The BRCA-1 gene is a well-known breast cancer susceptibility gene that normally plays a role in repairing breaks in DNA. However, when BRCA-1 is mutated, this repair function becomes disabled, leading to DNA replication errors, increased genomic instability(The instability of genetic material as a result of destructive chemical processes that lead to mutation) and ultimately cancer. Indeed, individuals with the BRCA-1 mutation have an increased risk of developing breast or ovarian cancer.

In 2002, Kawai and colleagues demonstrated that VEGF expression and secretion are controlled by a direct interaction involving BRCA-1 protein and the ER. Using normal breast tissue and breast cancer cell lines, the investigators showed that normal BRCA-1 protein suppressed the VEGF promoter (a proximal segment of DNA involved in turning on transcription of a gene) via the ER-α subunit and also regulated the secretion of VEGF from the cell. By contrast, mutated BRCA-1 was not able to suppress VEGF expression, leading to the conclusion that mutations in BRCA-1 could indirectly promote tumourigenesis(The process of initiating and promoting the development of a tumour) in part by causing dysregulation of VEGF function.10

References

  1. Schneider BP, Miller KD. J Clin Oncol 2005;23:1782–90
  2. Foekens JA, Peters HA, Grebenchtchikov N, et al. Cancer Res 2001;61:5407–14.
  3. Gasparini G, Toi M, Gion M, et al. J Natl Cancer Inst 1997;89:139–47.
  4. Konecny GE, Meng YG, Untch M, et al. Clin Cancer Res 2004;10:1706–16.
  5. Linderholm B, Grankvist K, Wilking N, et al. J Clin Oncol 2000;18:1423–31.
  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. Buteau-Lozano H, Ancelin M, Lardeux B, et al. Cancer Res 2002;62:4977–84.
  8. Fuckar D, Dekanic A, Stifter S, et al. Int J Surg Pathol 2006;14:49–55.
  9. Guo P, Fang Q, Tao HQ, et al. Cancer Res 2003;63:4684–91.
  10. Kawai H, Li H, Chun P, et al. Oncogene 2002;21:7730–9.
  11. Gasparini G, Toi M, Miceli R, et al. Cancer J Sci Am 1999;5:101–11.
  12. Yoshiji H, Gomez DE, Shibuya M, Thorgeirsson UP. Cancer Res 1996;56:2013–6.
  13. Brown LF, Berse B, Jackman RW, et al. Hum Pathol 1995;26:86–91.
  14. Jacobs EJ, Feigelson HS, Bain EB, et al. Breast Cancer Res 2006;8:R22.
  15. Van der Auwera I, Van Laere SJ, Van Den Eynden GG, et al. Clin Cancer Res 2004;10:7965–71.
  16. Relf M, LeJeune S, Scott PAE, et al. Cancer Res 1997;57:963–9.
  17. Toi M, Inada K, Suzuki H, Tominaga T. Breast Cancer Res Treat 1995;36:193–204.
  18. Guidi AJ, Schnitt SJ, Fischer L, et al. Cancer 1997;80:1945–53.
  19. Guidi AJ, Berry DA, Broadwater G, et al. J Natl Cancer Inst 2000;92:486–92.
  20. Osanai T, Wakita T, Gomi N, et al. Jpn J Clin Oncol 2003;33:14–16.

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