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MMP-9 expression varies according to molecular subtypes of breast cancer.

Yousef EM, Tahir MR, St-Pierre Y, Gaboury LA - BMC Cancer (2014)

Bottom Line: We next ascertained MMP-9 expression in both normal breast tissue and in human breast carcinoma tissue microarrays.Significant increase in MMP-9 expression was found in breast cancer cells where compared to normal breast tissue.Lastly, the clinical relevance of MMP-9 overexpression is strongly supported by its significant association with a higher incidence of metastasis and relapse.

View Article: PubMed Central - PubMed

Affiliation: Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Canada. louis.gaboury@umontreal.ca.

ABSTRACT

Background: In 2014, breast cancer remains a major cause of mortality worldwide mostly due to tumor relapse and metastasis. There is currently a great interest in identifying cancer biomarkers and signalling pathways mechanistically related to breast cancer progression. Matrix metalloproteinase-9 (MMP-9) is a member of matrix degrading enzymes involved in cancer development, invasion and metastasis. Our objective was to investigate MMP-9 expression in normal human breast tissue and to compare it to that of breast cancer of various histological grades and molecular subtypes. We also sought to correlate MMP-9 expression with the incidence of metastasis, survival rates and relapse in breast cancer patients.

Methods: MMP-9 was first studied using in silico analysis on available DNA microarray and RNA sequencing data of human breast cancer tissues and human breast cancer cell lines. We next ascertained MMP-9 expression in both normal breast tissue and in human breast carcinoma tissue microarrays.

Results: Significant increase in MMP-9 expression was found in breast cancer cells where compared to normal breast tissue. A positive correlation could also be established between elevated levels of MMP-9 and breast cancer of high histological grade. Furthermore, our results indicate that not only MMP-9 is differentially expressed between each molecular subset but also, more importantly MMP-9 overexpression revealed itself as a startling feature of triple-negative and HER2-positive breast cancers. Lastly, the clinical relevance of MMP-9 overexpression is strongly supported by its significant association with a higher incidence of metastasis and relapse.

Conclusions: Differential expression of MMP-9 reflects the extent of cellular differentiation in breast cancer cells and is closely related to the most aggressive subtypes of breast cancer. Hence, MMP-9 is a promising prognostic biomarker of high-grade breast cancer. In our opinion, MMP-9 expression could help segregate subsets of aggressive breast cancer into clinically meaningful subtypes.

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Expression ofMMP-9mRNA in human breast cancer cell lines.In silico analysis showing elevated MMP-9 mRNA expression levels in basal-like breast cancer cell lines (e.g. CAL85-1, HCC1395, HCC1143, DU4475, HCC1937, MDA-MB-231 and HCC38). Luminal breast cancer cell lines with HER2 amplification also display stronger MMP-9 mRNA expression (AU565, UAA-893 and HCC2218). MCF7 and KPL1 cell lines are the only luminal cell lines with mildly elevated MMP-9 mRNA expression. (B = basal, L = luminal, L + H = Luminal with HER2 amplification).
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Fig2: Expression ofMMP-9mRNA in human breast cancer cell lines.In silico analysis showing elevated MMP-9 mRNA expression levels in basal-like breast cancer cell lines (e.g. CAL85-1, HCC1395, HCC1143, DU4475, HCC1937, MDA-MB-231 and HCC38). Luminal breast cancer cell lines with HER2 amplification also display stronger MMP-9 mRNA expression (AU565, UAA-893 and HCC2218). MCF7 and KPL1 cell lines are the only luminal cell lines with mildly elevated MMP-9 mRNA expression. (B = basal, L = luminal, L + H = Luminal with HER2 amplification).

Mentions: The web application bc-GenExMiner [17] was used to compare the mRNA levels within each breast cancer molecular subtype on a dataset comprising 1210 microarrays. In brief, the gene expression data is given for those patients that could be assigned to a certain molecular subtype (robust classifications for 1210 patients). In Figure 1, the table indicates for each subtype the proportion of patients with low, intermediate, and high gene expression. Gene expression values were being beforehand split in order to form three equal groups. This means that “high expression” is the 1/3 of the patients with highest expression of MMP-9 and “low expression” is the lower 1/3 of the patients. As depicted in Figure 1, 57% of basal-like and 50% of HER2-positive breast cancer patients expressed high levels of MMP-9. In comparison, only 12% of those subtypes had a reduced expression of MMP-9. In sharp contrast, only 16% of the luminal A breast cancer subtype demonstrate increased expression of MMP-9. Data from the luminal B subtype indicate that 36% of patients have high levels of MMP-9 expression while approximately 30% maintained low levels of MMP-9. To expand on the results obtained from the microarray datasets, we investigated mRNA expression of MMP-9 in 51 breast cancer cell lines of different molecular subtypes [25–27] using publically available microarrays and mRNA sequencing breast cancer cell line datasets [18]. As shown in Figure 2, overexpression of MMP-9 was present in basal-like breast cancer cell lines CAL85-1, HCC1395, HCC1143, DU4475, HCC1937, MDA-MB-231 [28] and HCC38. Interestingly, many luminal breast cancer cell lines known to have HER2 gene amplification (AU565, UAA-893 and HCC2218) also exhibited high levels of MMP-9 expression. Notably, MCF7 and KPL1 cell lines were the only luminal cell lines that revealed a modest increase in MMP-9 expression above baseline levels [29].Figure 1


MMP-9 expression varies according to molecular subtypes of breast cancer.

Yousef EM, Tahir MR, St-Pierre Y, Gaboury LA - BMC Cancer (2014)

Expression ofMMP-9mRNA in human breast cancer cell lines.In silico analysis showing elevated MMP-9 mRNA expression levels in basal-like breast cancer cell lines (e.g. CAL85-1, HCC1395, HCC1143, DU4475, HCC1937, MDA-MB-231 and HCC38). Luminal breast cancer cell lines with HER2 amplification also display stronger MMP-9 mRNA expression (AU565, UAA-893 and HCC2218). MCF7 and KPL1 cell lines are the only luminal cell lines with mildly elevated MMP-9 mRNA expression. (B = basal, L = luminal, L + H = Luminal with HER2 amplification).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4150970&req=5

Fig2: Expression ofMMP-9mRNA in human breast cancer cell lines.In silico analysis showing elevated MMP-9 mRNA expression levels in basal-like breast cancer cell lines (e.g. CAL85-1, HCC1395, HCC1143, DU4475, HCC1937, MDA-MB-231 and HCC38). Luminal breast cancer cell lines with HER2 amplification also display stronger MMP-9 mRNA expression (AU565, UAA-893 and HCC2218). MCF7 and KPL1 cell lines are the only luminal cell lines with mildly elevated MMP-9 mRNA expression. (B = basal, L = luminal, L + H = Luminal with HER2 amplification).
Mentions: The web application bc-GenExMiner [17] was used to compare the mRNA levels within each breast cancer molecular subtype on a dataset comprising 1210 microarrays. In brief, the gene expression data is given for those patients that could be assigned to a certain molecular subtype (robust classifications for 1210 patients). In Figure 1, the table indicates for each subtype the proportion of patients with low, intermediate, and high gene expression. Gene expression values were being beforehand split in order to form three equal groups. This means that “high expression” is the 1/3 of the patients with highest expression of MMP-9 and “low expression” is the lower 1/3 of the patients. As depicted in Figure 1, 57% of basal-like and 50% of HER2-positive breast cancer patients expressed high levels of MMP-9. In comparison, only 12% of those subtypes had a reduced expression of MMP-9. In sharp contrast, only 16% of the luminal A breast cancer subtype demonstrate increased expression of MMP-9. Data from the luminal B subtype indicate that 36% of patients have high levels of MMP-9 expression while approximately 30% maintained low levels of MMP-9. To expand on the results obtained from the microarray datasets, we investigated mRNA expression of MMP-9 in 51 breast cancer cell lines of different molecular subtypes [25–27] using publically available microarrays and mRNA sequencing breast cancer cell line datasets [18]. As shown in Figure 2, overexpression of MMP-9 was present in basal-like breast cancer cell lines CAL85-1, HCC1395, HCC1143, DU4475, HCC1937, MDA-MB-231 [28] and HCC38. Interestingly, many luminal breast cancer cell lines known to have HER2 gene amplification (AU565, UAA-893 and HCC2218) also exhibited high levels of MMP-9 expression. Notably, MCF7 and KPL1 cell lines were the only luminal cell lines that revealed a modest increase in MMP-9 expression above baseline levels [29].Figure 1

Bottom Line: We next ascertained MMP-9 expression in both normal breast tissue and in human breast carcinoma tissue microarrays.Significant increase in MMP-9 expression was found in breast cancer cells where compared to normal breast tissue.Lastly, the clinical relevance of MMP-9 overexpression is strongly supported by its significant association with a higher incidence of metastasis and relapse.

View Article: PubMed Central - PubMed

Affiliation: Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Canada. louis.gaboury@umontreal.ca.

ABSTRACT

Background: In 2014, breast cancer remains a major cause of mortality worldwide mostly due to tumor relapse and metastasis. There is currently a great interest in identifying cancer biomarkers and signalling pathways mechanistically related to breast cancer progression. Matrix metalloproteinase-9 (MMP-9) is a member of matrix degrading enzymes involved in cancer development, invasion and metastasis. Our objective was to investigate MMP-9 expression in normal human breast tissue and to compare it to that of breast cancer of various histological grades and molecular subtypes. We also sought to correlate MMP-9 expression with the incidence of metastasis, survival rates and relapse in breast cancer patients.

Methods: MMP-9 was first studied using in silico analysis on available DNA microarray and RNA sequencing data of human breast cancer tissues and human breast cancer cell lines. We next ascertained MMP-9 expression in both normal breast tissue and in human breast carcinoma tissue microarrays.

Results: Significant increase in MMP-9 expression was found in breast cancer cells where compared to normal breast tissue. A positive correlation could also be established between elevated levels of MMP-9 and breast cancer of high histological grade. Furthermore, our results indicate that not only MMP-9 is differentially expressed between each molecular subset but also, more importantly MMP-9 overexpression revealed itself as a startling feature of triple-negative and HER2-positive breast cancers. Lastly, the clinical relevance of MMP-9 overexpression is strongly supported by its significant association with a higher incidence of metastasis and relapse.

Conclusions: Differential expression of MMP-9 reflects the extent of cellular differentiation in breast cancer cells and is closely related to the most aggressive subtypes of breast cancer. Hence, MMP-9 is a promising prognostic biomarker of high-grade breast cancer. In our opinion, MMP-9 expression could help segregate subsets of aggressive breast cancer into clinically meaningful subtypes.

Show MeSH
Related in: MedlinePlus