Elevated mammaglobin (h-MAM) expression in breast cancer is associated with clinical and biological features defining a less aggressive tumour phenotype

Abstract

Background Mammaglobin ( h-MAM ) is expressed mainly by breast epithelial cells, and this feature has been used to detect circulating breast cancer cells and occult metastases in sentinel axillary lymph nodes of breast cancer patients. However, the biological role of mammaglobin is completely unknown. Methods We studied 128 fresh-frozen breast cancer specimens by means of reverse transcriptase–polymerase chain reaction and quantified their h-MAM mRNA expression. This was then correlated with histological and nuclear grade, oestrogen and progesterone receptor expression, c-erb-B2 and mutant p53 expression, as well as with cellular proliferation measured by means of the Ki67 labelling index, DNA ploidy and S-phase, and finally with the presence or not of invaded axillary nodes in the mastectomy specimen. Results In the univariate analysis, high h-MAM expression (above the median for the whole group) correlated significantly ( P < 0.05) with oestrogen and progesterone receptor expression, diploid DNA content, low Ki67 labelling index, low nuclear grade and almost significantly ( P = 0.058) with the absence of axillary nodal invasion in the mastectomy specimen. In a final, multivariate model, only progesterone receptor expression, diploid DNA content and absence of nodal invasion were found to be independently associated with high h-MAM expression. Conclusion All of the features associated with mammaglobin expression reflect, without exception, a less aggressive tumour phenotype. Further studies are needed to clarify whether this is attributable to h-MAM expression itself, or to another mechanism of which mammaglobin expression forms part.

Detection of human mammaglobin mRNA in serial peripheral blood samples from patients with non-metastatic breast cancer is not predictive of disease recurrence

“…However, we detected an inverse association between mammaglobin mRNA expression in blood baseline samples and HER-2 overexpression or amplification in tumours. This is in contrast with the association of HER-2 overexpression and tumour aggressiveness [46] but in agreement with the reported lower expression of hMAM by breast tumour cells with a more aggressive phenotype documented by no expression of hormone receptors and high nuclear grade [19]. Thus, tumours with HER-2 overexpression may express lower or undetectable levels of hMAM transcript, which has not been studied before.…”

“…If later samples were included in the analysis, up to 48 months, patients with at least one hMAM positive sample had better disease-free survival than patients who never had hMAM positive blood samples, contrary to the study hypothesis. Mammaglobin expression by breast cancer cells seems to be correlated with indicators of better prognosis [19]. This may explain why we observed that hMAM positivity in baseline peripheral blood samples was more frequent in patients with HER2-negative tumours than in patients harbouring tumors with HER2 overexpression/ amplification.…”

“…Similarly, Ntoulia et al [41] also reported the expression of hMAM mRNA in 14/101 (13.9%) peripheral blood samples collected before the start of adjuvant chemotherapy, from patients with operable breast cancer. In contrast, Cerveira et al [19] documented peripheral blood hMAM positivity in 41% of breast cancer patients, by one-step RT-PCR. They hypothesized that the low percentages of positive results reported in other studies could be related to low sensitivity of the RT-PCR assay.…”

“…In contrast to cytokeratins, hMAM was reported to be exclusively expressed in mammary epithelium and overexpressed in some breast cancers, making it a potential useful RT-PCR target for breast cancer cell detection in hematopoietic products [17,18]. High levels of hMAM in primary breast tumours reflect a less aggressive tumour phenotype and are correlated with the expression of estrogen and progesterone receptors, diploid DNA content, low Ki67 labelling index, low nuclear grade and absence of axillary nodal invasion [19]. The evaluation of hMAM as a molecular marker of lymph node metastases demonstrated the utility of hMAM-specific PCR in the detection of micrometastases [20][21][22][23][24][25].…”

Relevance of circulating tumor cells, extracellular nucleic acids, and exosomes in breast cancer

“…This over-expression did not appear to correlate with histology, tumor grade, tumor stage, or ER/PR status. A more recent study reported high MGB1 levels in primary breast cancers to be indicative of a less aggressive tumor phenotype and correlating with the expression of ER and PR, low Ki-67 labeling and absence of nodal invasion [133]. There has, so far, been no reported documentation of circulating transcripts of MGB1, however, MGB1 protein has been detected in sera of breast cancer patients [134,135].…”