Differential expression of PMCA2 mRNA isoforms in a cohort of Spanish patients with breast tumor types

Abstract

The present study examined the mRNA expression levels of different isoforms of the plasma membrane calcium ATPase 2 (PMCA2) gene generated by alternative splicing at the first intracellular loop (site A) and C-terminal region (site C) in 85 human breast cancer tumor and 69 adjacent non-tumor tissues. Associations were identified between the expression of PMCA2 splice isoforms and the following clinical variables: Estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) status, tumor size, staging and histological classification, and lymph node status. Transcripts including splice site A or splice site C were amplified by reverse transcription-quantitative polymerase chain reaction using PMCA2 isoform-specific primers. Tumor and adjacent tissues were determined to express the different PMCA2 splice isoforms 2w, 2× and 2z (site A), and 2b (site C). The mRNA levels for these variants indicated high biological variability, but increased expression was observed in breast tumor tissues, compared with in adjacent tissues. Significantly increased PMCA2×/b expression levels were detected in breast tumor tissues histologically classified as lobulillar, compared with in ductal-types breast tumor tissues (P<0.028). Furthermore, PMCA2z expression was significantly associated with PR status (P<0.024, compared with in PR-negative tumor tissues), and PMCA2w expression was significantly associated with ER status (P<0.048, increased in ER-positive tumor tissues, compared with ER-negative tumor tissues). Finally, PMCA2b was overexpressed in HER2-positive tumor tissues, compared with in HER2-negative tumor tissues (P<0.014). The data demonstrated the differential mRNA expression of a number of splice site A and C variants of PMCA2 in breast tumor and adjacent tissues, depending on tumor hormone receptor status and histological classification. In agreement with previous data, PMCA2b was overexpressed in HER2-positive tumor tissues, indicating that high mRNA levels of this variant could be a marker of poor prognosis.

Subtype specific targeting of calcium signaling in breast cancer

“…Of the four human isoforms, PMCA2 is reversibly induced in lactating epithelial mammary gland under normal physiological conditions, but is abnormally overexpressed in breast cancer cells [42,43]. Interestingly, a study of 85 human breast tumors in comparison with 69 adjacent non-tumor tissue revealed associations between specific splice variants of PMCA2 and clinical variables, including receptor status, tumor size, metastasis and stage [44]. Splice variants at the N-and C-termini of PMCA2 are known to alter apical to basal localization of the pump and affinity for the regulatory protein calmodulin suggesting that pump activity is tailored for specific outcomes in cancer cells [44].…”

“…Interestingly, a study of 85 human breast tumors in comparison with 69 adjacent non-tumor tissue revealed associations between specific splice variants of PMCA2 and clinical variables, including receptor status, tumor size, metastasis and stage [44]. Splice variants at the N-and C-termini of PMCA2 are known to alter apical to basal localization of the pump and affinity for the regulatory protein calmodulin suggesting that pump activity is tailored for specific outcomes in cancer cells [44]. High levels of PMCA2 were found to co-express strongly with HER2 and correlate with poor survival prognosis.…”

Structure, Function and Regulation of the Plasma Membrane Calcium Pump in Health and Disease

“…In breast cancer, the expression of PMCA2 is significantly increased and colocalizes with the human epidermal growth factor receptor 2 (HER2) in actin-rich membrane microdomains [102] (Table 1). By investigating several patients, Romero-Lorca et al reported the increased expression level of various spliced isoforms of PMCA2 mRNA in breast cancer tumor cells, which correlated with the expression of different growth factor receptors [103].…”