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Immunohistochemical expression of insulin-like growth factor binding protein-3 in invasive breast cancers and ductal carcinoma in situ: implications for clinicopathology and patient outcome.

Vestey SB, Perks CM, Sen C, Calder CJ, Holly JM, Winters ZE - Breast Cancer Res. (2004)

Bottom Line: Although IGFBP-3 expression was not an independent prognosticator, IGFBP-3-positive breast cancers may have shorter disease-free and overall survivals, although these did not reach statistical significance.There are trends between high levels of IGFBP-3 and poor prognostic features, suggesting that IGFBP-3 is a potential mitogen.IGFBP-3 is not an independent prognosticator for overall survival or disease-free survival, to reflect its dual effects on breast cancer growth regulated by complex pathways in vivo that may relate to its interactions with other growth factors.

View Article: PubMed Central - HTML - PubMed

Affiliation: University of Bristol, Department of Clinical Sciences at South Bristol-Surgery, Bristol Royal Infirmary, Bristol, UK. vesteyhaynes@hotmail.com

ABSTRACT

Introduction: Insulin-like growth factor binding protein-3 (IGFBP-3) differentially modulates breast epithelial cell growth through insulin-like growth factor (IGF)-dependent and IGF-independent pathways and is a direct (IGF-independent) growth inhibitor as well as a mitogen that potentiates EGF (epidermal growth factor) and interacts with HER-2. Previously, high IGFBP-3 levels in breast cancers have been determined by enzyme-linked immunosorbent assay and immunoradiometric assay methods. In vitro, IGFBP-3's mechanisms of action may involve cell membrane binding and nuclear translocation. To evaluate tumour-specific IGFBP-3 expression and its subcellular localisation, this study examined immunohistochemical IGFBP-3 expression in a series of invasive ductal breast cancers (IDCs) with synchronous ductal carcinomas in situ (DCIS) in relation to clinicopathological variables and patient outcome.

Methods: Immunohistochemical expression of IGFBP-3 was evaluated with the sheep polyclonal antiserum (developed in house) with staining performed as described previously.

Results: IGFBP-3 was evaluable in 101 patients with a variable pattern of cytoplasmic expression (positivity of 1+/2+ score) in 85% of invasive and 90% of DCIS components. Strong (2+) IGFBP-3 expression was evident in 32 IDCs and 40 cases of DCIS. A minority of invasive tumours (15%) and DCIS (10%) lacked IGFBP-3 expression. Nuclear IGFBP-3 expression was not detectable in either invasive cancers or DCIS, with a consistent similarity in IGFBP-3 immunoreactivity in IDCs and DCIS. Positive IGFBP-3 expression showed a possible trend in association with increased proliferation (P = 0.096), oestrogen receptor (ER) negativity (P = 0.06) and HER-2 overexpression (P = 0.065) in invasive tumours and a strong association with ER negativity (P = 0.037) in DCIS. Although IGFBP-3 expression was not an independent prognosticator, IGFBP-3-positive breast cancers may have shorter disease-free and overall survivals, although these did not reach statistical significance.

Conclusions: Increased breast epithelial IGFBP-3 expression is a feature of tumorigenesis with cytoplasmic immunoreactivity in the absence of significant nuclear localisation in IDCs and DCIS. There are trends between high levels of IGFBP-3 and poor prognostic features, suggesting that IGFBP-3 is a potential mitogen. IGFBP-3 is not an independent prognosticator for overall survival or disease-free survival, to reflect its dual effects on breast cancer growth regulated by complex pathways in vivo that may relate to its interactions with other growth factors.

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Examples of IGFBP-3 immunoreactivity in infiltrating ductal carcinoma of the breast with concomitant DCIS. Immunostaining was performed as described in the Methods section, and nuclei were counterstained with haematoxylin. (a) A tumour showing cytoplasmic IGFBP-3 expression in invasive ductal cancer. (b) A similar cytoplasmic IGFBP-3 positivity in concomitant DCIS. High-power magnification (original magnification × 400).
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Figure 1: Examples of IGFBP-3 immunoreactivity in infiltrating ductal carcinoma of the breast with concomitant DCIS. Immunostaining was performed as described in the Methods section, and nuclei were counterstained with haematoxylin. (a) A tumour showing cytoplasmic IGFBP-3 expression in invasive ductal cancer. (b) A similar cytoplasmic IGFBP-3 positivity in concomitant DCIS. High-power magnification (original magnification × 400).

Mentions: IGFBP-3 immunoreactivity was evaluable in 101 (98%) cases of IDCs and in 102 cases of DCIS, and scored positively (1+/2+) as a homogeneous cytoplasmic expression in 86 (85%) of invasive and 92 (90%) of DCIS components (Fig. 1; Tables 1 and 2). Strong (2+) IGFBP-3 expression was seen in 32 invasive breast cancers and 40 cases of DCIS. A weak/moderate (1+) expression of IGFBP-3 was evident in the majority of invasive (n = 54) and DCIS (n = 52) components. There was no clear evidence of nuclear IGFBP-3 expression on IHC in IDC or DCIS. Consistently low levels of IGFBP-3 were evident throughout the stroma, without strong expression except in vascular endothelial cells. A comparison showed that the levels of IGFBP-3 expression in DCIS were similar to those in invasive disease (Table 2).


Immunohistochemical expression of insulin-like growth factor binding protein-3 in invasive breast cancers and ductal carcinoma in situ: implications for clinicopathology and patient outcome.

Vestey SB, Perks CM, Sen C, Calder CJ, Holly JM, Winters ZE - Breast Cancer Res. (2004)

Examples of IGFBP-3 immunoreactivity in infiltrating ductal carcinoma of the breast with concomitant DCIS. Immunostaining was performed as described in the Methods section, and nuclei were counterstained with haematoxylin. (a) A tumour showing cytoplasmic IGFBP-3 expression in invasive ductal cancer. (b) A similar cytoplasmic IGFBP-3 positivity in concomitant DCIS. High-power magnification (original magnification × 400).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC1064109&req=5

Figure 1: Examples of IGFBP-3 immunoreactivity in infiltrating ductal carcinoma of the breast with concomitant DCIS. Immunostaining was performed as described in the Methods section, and nuclei were counterstained with haematoxylin. (a) A tumour showing cytoplasmic IGFBP-3 expression in invasive ductal cancer. (b) A similar cytoplasmic IGFBP-3 positivity in concomitant DCIS. High-power magnification (original magnification × 400).
Mentions: IGFBP-3 immunoreactivity was evaluable in 101 (98%) cases of IDCs and in 102 cases of DCIS, and scored positively (1+/2+) as a homogeneous cytoplasmic expression in 86 (85%) of invasive and 92 (90%) of DCIS components (Fig. 1; Tables 1 and 2). Strong (2+) IGFBP-3 expression was seen in 32 invasive breast cancers and 40 cases of DCIS. A weak/moderate (1+) expression of IGFBP-3 was evident in the majority of invasive (n = 54) and DCIS (n = 52) components. There was no clear evidence of nuclear IGFBP-3 expression on IHC in IDC or DCIS. Consistently low levels of IGFBP-3 were evident throughout the stroma, without strong expression except in vascular endothelial cells. A comparison showed that the levels of IGFBP-3 expression in DCIS were similar to those in invasive disease (Table 2).

Bottom Line: Although IGFBP-3 expression was not an independent prognosticator, IGFBP-3-positive breast cancers may have shorter disease-free and overall survivals, although these did not reach statistical significance.There are trends between high levels of IGFBP-3 and poor prognostic features, suggesting that IGFBP-3 is a potential mitogen.IGFBP-3 is not an independent prognosticator for overall survival or disease-free survival, to reflect its dual effects on breast cancer growth regulated by complex pathways in vivo that may relate to its interactions with other growth factors.

View Article: PubMed Central - HTML - PubMed

Affiliation: University of Bristol, Department of Clinical Sciences at South Bristol-Surgery, Bristol Royal Infirmary, Bristol, UK. vesteyhaynes@hotmail.com

ABSTRACT

Introduction: Insulin-like growth factor binding protein-3 (IGFBP-3) differentially modulates breast epithelial cell growth through insulin-like growth factor (IGF)-dependent and IGF-independent pathways and is a direct (IGF-independent) growth inhibitor as well as a mitogen that potentiates EGF (epidermal growth factor) and interacts with HER-2. Previously, high IGFBP-3 levels in breast cancers have been determined by enzyme-linked immunosorbent assay and immunoradiometric assay methods. In vitro, IGFBP-3's mechanisms of action may involve cell membrane binding and nuclear translocation. To evaluate tumour-specific IGFBP-3 expression and its subcellular localisation, this study examined immunohistochemical IGFBP-3 expression in a series of invasive ductal breast cancers (IDCs) with synchronous ductal carcinomas in situ (DCIS) in relation to clinicopathological variables and patient outcome.

Methods: Immunohistochemical expression of IGFBP-3 was evaluated with the sheep polyclonal antiserum (developed in house) with staining performed as described previously.

Results: IGFBP-3 was evaluable in 101 patients with a variable pattern of cytoplasmic expression (positivity of 1+/2+ score) in 85% of invasive and 90% of DCIS components. Strong (2+) IGFBP-3 expression was evident in 32 IDCs and 40 cases of DCIS. A minority of invasive tumours (15%) and DCIS (10%) lacked IGFBP-3 expression. Nuclear IGFBP-3 expression was not detectable in either invasive cancers or DCIS, with a consistent similarity in IGFBP-3 immunoreactivity in IDCs and DCIS. Positive IGFBP-3 expression showed a possible trend in association with increased proliferation (P = 0.096), oestrogen receptor (ER) negativity (P = 0.06) and HER-2 overexpression (P = 0.065) in invasive tumours and a strong association with ER negativity (P = 0.037) in DCIS. Although IGFBP-3 expression was not an independent prognosticator, IGFBP-3-positive breast cancers may have shorter disease-free and overall survivals, although these did not reach statistical significance.

Conclusions: Increased breast epithelial IGFBP-3 expression is a feature of tumorigenesis with cytoplasmic immunoreactivity in the absence of significant nuclear localisation in IDCs and DCIS. There are trends between high levels of IGFBP-3 and poor prognostic features, suggesting that IGFBP-3 is a potential mitogen. IGFBP-3 is not an independent prognosticator for overall survival or disease-free survival, to reflect its dual effects on breast cancer growth regulated by complex pathways in vivo that may relate to its interactions with other growth factors.

Show MeSH
Related in: MedlinePlus