Abstract
The Proline-, glutamic acid- and leucine-rich protein 1 (PELP1) is an estrogen receptor (ER) coactivator and a proto-oncogene known to be deregulated in endocrine cancers. In breast cancer, PELP1 overexpression has been associated with endocrine therapy resistance. Although PELP1 is known to be regulated by estrogens in vitro, its association with estrogen levels within the tissue of breast cancer patients has not previously been assessed. Here, we determined PELP1 mRNA expression levels in paired samples of normal and malignant breast tissue obtained from 32 postmenopausal and 11 premenopausal women. In the total sample set, PELP1 levels were higher in tumors compared to normal breast tissue (P = 0.041). Among postmenopausal women, PELP1 tumor levels correlated positively with estrone (E1) and estradiol (E2) levels in both normal tissue (r = 0.543, P = 0.003 and r = 0.601, P = 0.001, respectively) and plasma (r = 0.392, P = 0.053 and r = 0.403, P = 0.046, respectively). Analyzing all ER+ tumors (n = 26), PELP1 correlated positively with E1 and E2 in tumor tissue (r = 0.562, P = 0.003 and r = 0.411, P = 0.037, respectively) and normal tissue (r = 0.461, P = 0.018 and r = 0.427, P = 0.030, respectively) in addition to plasma E1, E2 and estrone sulphate (E1S) concentrations (r = 0.576, P = 0.003, r = 0.456, P = 0.025 and r = 0.406, P = 0.049, respectively). Finally, PELP1 correlated positively with ER mRNA (ESR1) (r = 0.553, P = 0.026) in ER+ tumors, whereas a negative association between PELP1 and ESR1 (r = -0.733, P = 0.010) was observed in ER- breast tumors. Taken together, tumor PELP1 mRNA expression is associated with estrogen levels in breast cancer, suggesting a potentially important role of PELP1 in ER+ breast cancer growth in vivo.
Highlights
The human estrogen receptor (ER) plays an important role in development and progression of breast cancer
The Proline, glutamic acid- and leucine-rich protein 1 (PELP1) is an estrogen receptor (ER) coactivator and a proto-oncogene known to be deregulated in endocrine cancers
In malignant breast tissue geometric mean of PELP1 expression was 1.37 (95% Confidence Interval (CI): 1.22–1.53), compared to normal tissue with geo mean of 1.25
Summary
The human estrogen receptor (ER) plays an important role in development and progression of breast cancer. ER coregulators have been shown to play a role in endocrine responsiveness and development of resistance to endocrine treatment [3,4,5]. PELP1 is overexpressed in 60–80% of breast tumors [6,7,8,9] and plays important roles in both ER genomic and non-genomic signaling [10, 11]. The proto-oncogenic functions of PELP1 involve different cellular processes including epigenetic modifications leading to ER transactivation and breast cancer progression [12,13,14]. PELP1 activates kinase cascades in the cytoplasm such as MAPK activation via c-Src and PI3K signaling [9, 11, 15, 16]
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