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. 2023 Jun 28;18(6):e0287062.
doi: 10.1371/journal.pone.0287062. eCollection 2023.

FMRP expression in primary breast tumor cells correlates with recurrence and specific site of metastasis

E Caredda  1   2 , G Pedini  1 , F D'Amico  3   4 , M G Scioli  3 , L Pacini  1   5 , P Orsaria  6 , G Vanni  7 , O C Buonomo  7 , A Orlandi  3 , C Bagni  1   8 , L Palombi  1
Affiliations

FMRP expression in primary breast tumor cells correlates with recurrence and specific site of metastasis

E Caredda et al. PLoS One. .

Abstract

Breast cancer is the most common cancer among women worldwide. Molecular and clinical evidence indicated that Fragile X Messenger Ribonucleoprotein 1 (FMRP) plays a role in different types of cancer, including breast cancer. FMRP is an RNA binding protein that regulates the metabolism of a large group of mRNAs coding for proteins involved in both neural processes and in epithelial-mesenchymal transition, a pivotal mechanism that in cancer is associated to tumor progression, aggressiveness and chemoresistance. Here, we carried out a retrospective case-control study of 127 patients, to study the expression of FMRP and its correlation with metastasis formation in breast cancer. Consistent with previous findings, we found that FMRP levels are high in tumor tissue. Two categories have been analyzed, tumor with no metastases (referred as control tumors, 84 patients) and tumor with distant metastatic repetition, (referred as cases, 43 patients), with a follow-up of 7 years (mean). We found that FMRP levels were lower in both the nuclei and the cytoplasm in the cases compared to control tumors. Next, within the category cases (tumor with metastases) we evaluated FMRP expression in the specific sites of metastasis revealing a nuclear staining of FMRP. In addition, FMRP expression in both the nuclear and cytoplasmic compartment was significantly lower in patients who developed brain and bone metastases and higher in hepatic and pulmonary sites. While further studies are required to explore the underlying molecular mechanisms of FMRP expression and direct or inverse correlation with the secondary metastatic site, our findings suggest that FMRP levels might be considered a prognostic factor for site-specific metastasis.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. FMRP expression in breast cancer patients in controls (without metastases) and cases (with metastases).
Representative microphotographs of α-FMRP immunostaining performed on primary breast cancer tissue sections from Controls (no metastases) and Cases (metastases). No metastatic tissue was analyzed in our study. Images of two different molecular subtypes, luminal B/HER2- and basal (triple negative), are included for illustration. As shown, FMRP is highly expressed in Controls compared to Cases, both in the nuclei (arrows) and in the cytoplasm of tumor cells. As described in the text, cytoplasmic and nuclear expression are strongly correlated (p < 0.001). Arrows indicate nuclear expression. Surrounding stromal cells and connective tissue are negative for FMRP staining. Scale bar = 100 μm.
Fig 2
Fig 2. FMRP expression in the cytoplasm of cancer cells in controls and cases.
The histogram represents FMRP expression in the cytoplasm from Controls in blue and Cases in red. The frequency of occurrence (number of patients characterized by a defined FMRP expression score) was plotted versus FMRP expression. FMRP levels were determined by IHC using a grading system in arbitrary units (absence of positivity (0), weak (1), moderate (2), and strong (3)). The expression of FMRP in the cytoplasm shows an inverse correlation in Cases versus Controls (Fisher’s exact test, p < 0.001).
Fig 3
Fig 3. Kaplan-Meier univariate and multivariate survival curves based on FMRP cytoplasmic staining.
As survival rate we considered the time of metastasis appearance (not death of the patient) during the entire length of the study (mean 7 years). In the curve, each step is an event (metastasis), each dash the end of an observation time (censored). We followed the association between absence (0), low or high (1) expression of cytoplasmic FMRP and the occurrence of metastasis over time. Left panel, Kaplan-Meier univariate survival analysis shows the curve for the absence (blue) and presence (green) of FMRP expression. Right panel, Kaplan Meier multivariate survival analysis shows the same results. Kaplan-Meier univariate and multivariate survival analysis showed that the absence or lower FMRP cytoplasmic expression had more frequent metastasis (p < 0.001).
Fig 4
Fig 4. Metastasis occurrence stratified for FMRP cytoplasmic expression categories.
Survival tests were performed considering the appearance of metastasis (and not death) during the study (mean 7 years). We followed the association between the scoring of cytoplasmic FMRP expression (absence of positivity (0), weak (1), moderate (2), and strong (3)) and the occurrence of metastasis over time. We have observed an increasing association between cytoplasmic FMRP levels (from 3 = highest, to 0 = absence) and the risk of developing metastasis. Cox regression bivariate analysis recognized class 0 cytoplasmic expression of FMRP as the highest risk for metastatic outcome (beta exponent as OR = 3.5; 95% CI: 1.85–6.65 and p < 0.001).
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This work was supported by Telethon GGP20137 and PRIN 201789LFKB MIUR, to CB. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Other Authors received no specific funding for this work.