Limits...
Low calpain-9 is associated with adverse disease-specific survival following endocrine therapy in breast cancer.

Davis J, Martin SG, Patel PM, Green AR, Rakha EA, Ellis IO, Storr SJ - BMC Cancer (2014)

Bottom Line: Low expression of calpain-9 was associated with patients over 40 years of age (P = 0.025), smaller tumour size (P = 0.001), lower tumour stage (P = 0.009), a more favourable Nottingham Prognostic Index value (P = 0.002) and positive oestrogen receptor status (P = 0.014).Calpain-9 expression was not associated with survival in the total patient cohort, however low calpain-9 expression was associated with adverse survival in patients who received endocrine therapy (P = 0.033), which remained significant in multivariate Cox regression analysis accounting for potential confounding factors (hazard ratio (HR) = 0.56, 95% confidence interval (95% CI) = 0.36-0.89, P = 0.013).Low calpain-9 expression was also associated with adverse survival in patients with an intermediate Nottingham Prognostic Index value (P = 0.009), and remained so in multivariate analysis (HR = 0.54, 95% CI = 0.36-0.82, P = 0.003).

View Article: PubMed Central - PubMed

Affiliation: Academic Clinical Oncology, University of Nottingham, Division of Cancer and Stem Cells, Nottingham University Hospitals NHS Trust, City Hospital Campus, Nottingham NG5 1 PB, UK. sarah.storr@nottingham.ac.uk.

ABSTRACT

Background: The calpains are intracellular cysteine proteases that function in a variety of important cellular functions, including signalling, motility, apoptosis and survival. In breast cancer high calpain-1 and calpain-2 expression has been associated with adverse clinical outcome. Calpain-9 was thought to be exclusively expressed in the digestive tract; however recent studies have shown that this protein is also expressed in breast tissue.

Methods: We investigated the expression of calpain-9 in a large cohort of early stage breast cancer patients (n = 783) using immunohistochemistry on a tissue microarray. Patients had long-term follow-up information available for analysis.

Results: Low expression of calpain-9 was associated with patients over 40 years of age (P = 0.025), smaller tumour size (P = 0.001), lower tumour stage (P = 0.009), a more favourable Nottingham Prognostic Index value (P = 0.002) and positive oestrogen receptor status (P = 0.014). Calpain-9 expression was not associated with survival in the total patient cohort, however low calpain-9 expression was associated with adverse survival in patients who received endocrine therapy (P = 0.033), which remained significant in multivariate Cox regression analysis accounting for potential confounding factors (hazard ratio (HR) = 0.56, 95% confidence interval (95% CI) = 0.36-0.89, P = 0.013). Low calpain-9 expression was also associated with adverse survival in patients with an intermediate Nottingham Prognostic Index value (P = 0.009), and remained so in multivariate analysis (HR = 0.54, 95% CI = 0.36-0.82, P = 0.003).

Conclusions: This study suggests that calpain-9 may play a role in breast cancer and that low expression is associated with poorer patient clinical outcome following endocrine therapy. Validation studies are warranted as determining expression of calpain-9 may provide important prognostic information.

Show MeSH

Related in: MedlinePlus

Representative photomicrographs following immunohistochemical staining of (A) high calpain-9 and (B) low calpain-9 staining. Photomicrographs are shown at 100x magnification with 200x magnification inset box where scale shows 100 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC4364321&req=5

Fig1: Representative photomicrographs following immunohistochemical staining of (A) high calpain-9 and (B) low calpain-9 staining. Photomicrographs are shown at 100x magnification with 200x magnification inset box where scale shows 100 μm.

Mentions: Calpain-9 demonstrated cytoplasmic staining with heterogeneity in intensity between adjacent tumour cells ranging from weak to strong staining. Calpain-9 staining had a median H-score of 40 and ranged between 0 and 220. Photomicrographs showing representative staining patterns are shown in Figure 1. A total of 783 breast cancer specimens were analysed using a tissue microarray; of which 58.1% (455/783) were invasive ductal carcinomas, 17.0% (133/783) were tubular mixed, 6.5% (51/783) were classic lobular, all other subcategories accounted for less than 5% of the studied cohort. Calpain-9 H-scores were dichotomised using X-Tile software into low and high immunoreactivity based on patient survival; X-tile generated an H score cut point of 40 with 465 (59.4%) cases having a low score. A proportion of sample cores within the TMA were unable to be assessed as they were missing or cores had an insufficient number of tumour cells.Figure 1


Low calpain-9 is associated with adverse disease-specific survival following endocrine therapy in breast cancer.

Davis J, Martin SG, Patel PM, Green AR, Rakha EA, Ellis IO, Storr SJ - BMC Cancer (2014)

Representative photomicrographs following immunohistochemical staining of (A) high calpain-9 and (B) low calpain-9 staining. Photomicrographs are shown at 100x magnification with 200x magnification inset box where scale shows 100 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4364321&req=5

Fig1: Representative photomicrographs following immunohistochemical staining of (A) high calpain-9 and (B) low calpain-9 staining. Photomicrographs are shown at 100x magnification with 200x magnification inset box where scale shows 100 μm.
Mentions: Calpain-9 demonstrated cytoplasmic staining with heterogeneity in intensity between adjacent tumour cells ranging from weak to strong staining. Calpain-9 staining had a median H-score of 40 and ranged between 0 and 220. Photomicrographs showing representative staining patterns are shown in Figure 1. A total of 783 breast cancer specimens were analysed using a tissue microarray; of which 58.1% (455/783) were invasive ductal carcinomas, 17.0% (133/783) were tubular mixed, 6.5% (51/783) were classic lobular, all other subcategories accounted for less than 5% of the studied cohort. Calpain-9 H-scores were dichotomised using X-Tile software into low and high immunoreactivity based on patient survival; X-tile generated an H score cut point of 40 with 465 (59.4%) cases having a low score. A proportion of sample cores within the TMA were unable to be assessed as they were missing or cores had an insufficient number of tumour cells.Figure 1

Bottom Line: Low expression of calpain-9 was associated with patients over 40 years of age (P = 0.025), smaller tumour size (P = 0.001), lower tumour stage (P = 0.009), a more favourable Nottingham Prognostic Index value (P = 0.002) and positive oestrogen receptor status (P = 0.014).Calpain-9 expression was not associated with survival in the total patient cohort, however low calpain-9 expression was associated with adverse survival in patients who received endocrine therapy (P = 0.033), which remained significant in multivariate Cox regression analysis accounting for potential confounding factors (hazard ratio (HR) = 0.56, 95% confidence interval (95% CI) = 0.36-0.89, P = 0.013).Low calpain-9 expression was also associated with adverse survival in patients with an intermediate Nottingham Prognostic Index value (P = 0.009), and remained so in multivariate analysis (HR = 0.54, 95% CI = 0.36-0.82, P = 0.003).

View Article: PubMed Central - PubMed

Affiliation: Academic Clinical Oncology, University of Nottingham, Division of Cancer and Stem Cells, Nottingham University Hospitals NHS Trust, City Hospital Campus, Nottingham NG5 1 PB, UK. sarah.storr@nottingham.ac.uk.

ABSTRACT

Background: The calpains are intracellular cysteine proteases that function in a variety of important cellular functions, including signalling, motility, apoptosis and survival. In breast cancer high calpain-1 and calpain-2 expression has been associated with adverse clinical outcome. Calpain-9 was thought to be exclusively expressed in the digestive tract; however recent studies have shown that this protein is also expressed in breast tissue.

Methods: We investigated the expression of calpain-9 in a large cohort of early stage breast cancer patients (n = 783) using immunohistochemistry on a tissue microarray. Patients had long-term follow-up information available for analysis.

Results: Low expression of calpain-9 was associated with patients over 40 years of age (P = 0.025), smaller tumour size (P = 0.001), lower tumour stage (P = 0.009), a more favourable Nottingham Prognostic Index value (P = 0.002) and positive oestrogen receptor status (P = 0.014). Calpain-9 expression was not associated with survival in the total patient cohort, however low calpain-9 expression was associated with adverse survival in patients who received endocrine therapy (P = 0.033), which remained significant in multivariate Cox regression analysis accounting for potential confounding factors (hazard ratio (HR) = 0.56, 95% confidence interval (95% CI) = 0.36-0.89, P = 0.013). Low calpain-9 expression was also associated with adverse survival in patients with an intermediate Nottingham Prognostic Index value (P = 0.009), and remained so in multivariate analysis (HR = 0.54, 95% CI = 0.36-0.82, P = 0.003).

Conclusions: This study suggests that calpain-9 may play a role in breast cancer and that low expression is associated with poorer patient clinical outcome following endocrine therapy. Validation studies are warranted as determining expression of calpain-9 may provide important prognostic information.

Show MeSH
Related in: MedlinePlus