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, 10, 161-168
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Intracellular Aggregated TRPV1 Is Associated With Lower Survival in Breast Cancer Patients

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Intracellular Aggregated TRPV1 Is Associated With Lower Survival in Breast Cancer Patients

Carlo Lozano et al. Breast Cancer (Dove Med Press).

Abstract

Background: Breast cancer is a malignant disease that represents an important public health burden. The description of new molecular markers can be important to diagnosis, classification, and treatment. Transient receptor potential vanilloid 1 (TRPV1) polymodal channel is expressed in different neoplastic tissues and cell lines of breast cancer and associated with the regulation of tumor growth, tumor neurogenesis, cancer pain, and malignant progression of cancer. In primary and metastatic breast cancer tumors, TRPV1 is expressed during neoplastic transformation, invasive behavior, and resistance to cytotoxic therapy.

Objective: The objective of this study was to describe the subcellular distribution of TRPV1 in invasive breast carcinomas and its association with survival.

Methods: In 33 cases of invasive breast carcinomas, we identified immunohistochemical and immunofluorescent expression patterns of TRPV1 compared to healthy breast tissue. We characterized the expression of TRPV1 induced by estrogens in breast cancer cell lines MCF-7 and MDA to establish a model of the TRPV1-estrogen relationship regarding the malignant potential. We examined the association of TRPV1 patterns with patients' survival with the Kaplan-Meyer model, using the log-rank test at 5 years of follow-up. The relation of TRPV1 expression patterns to the St. Gallen breast cancer subtypes was also tested.

Results: Based on immunohistochemical expression pattern of TRPV1, we distinguished two main categories of breast cancer tissue, a "classical category" that exhibited diffuse expression of the channel and a "non-classical category" that expressed the channel in aggregates at the ER/Golgi and/or surrounding these structures. The classical pattern of TRPV1 was associated with a higher survival rate. In breast cancer cell lines, increasing doses of estrogens induced increased TRPV1 expression with nonclassical patterns at higher doses via a mechanism dependent on ER α.

Conclusion: The expression and distribution of TRPV1 in invasive breast carcinomas may be considered as a biomarker for prognosis of the disease and a probable therapeutic target.

Keywords: breast cancer; breast cancer prognosis; capsaicin receptors; immunohistochemistry; vanilloid receptors.

Conflict of interest statement

Disclosure The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
Transcription and subcellular distribution of TRPV1 in MDA-MB-231 and MCF-7 cell lines. Notes: (A) TRPV1 mRNA expression in MDA-MB-231 and MCF-7 by qPCR did not reveal any statistical difference. (B) Different abundance and distribution of TRPV1 in MDA-MB-231 and MCF-7. Image magnification: images was obtained in 100· (optical). After analysis process, digital magnification was 1.25·. (C) Colocalization analysis results. In MDA-MB-231, most of TRPV1 protein followed the same subcellular distribution as the ER, whereas the classical pattern in MCF-7 did not colocalize with the ER/Golgi mark. (D) MDA-MB-231 and MCF-7 exhibited different expressions of ERs. In MDA-MB-231, qPCR experiments showed expression of ERβ only, whereas MCF-7 expressed both ERα and ERβ (P<0.05). (E) The transcription of TRPV1 in MCF-7 was induced by estradiol and blocked by the antagonist of ER ICI 182780. *p>0.05. (F) In MCF-7, TRPV1 did not present significant colocalization with any of the masks automatically generated, ie, plasma membrane, cytosol, and nucleus. This pattern can be classified as classical. On the other hand, MDA-MB-231 colocalizes more proteins in the cytosol mask, this pattern being classified as nonclassical. Abbreviation: qPCR, quantitative PCR.
Figure 2
Figure 2
Nonclassical pattern of TRPV1 identifies higher malignancy breast carcinomas. Notes: (A) The immunofluorescence of C-TRPV1 and N-TRPV1 antibodies confirmed the expression of TRPV1 in breast cancer, with a diffuse expression pattern. (B) The immunohistochemical detection of TRPV1 shows a classical pattern at the plasma membrane and cytosol, and a nonclassical pattern with aggregates of TRPV1 at the ER/Golgi and/or a relatively diffuse distribution of the channel at the surrounding cytosol. (C) The classical TRPV1 pattern was more frequent in lower malignancy St. Gallen subtypes luminal A + luminal B compared to the most aggressive subtypes Her 2 + triple negative. (D) Survival curves according to the pattern of TRPV1 subcellular distribution.

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