Inositol (1,4,5)-Trisphosphate Receptors in Invasive Breast Cancer: A New Prognostic Tool?

Arthur Foulon,Lise Rodat-Despoix,Halima Ouadid-Ahidouch,Henri Sevestre,Eva Brabencova,Pierre Rybarczyk,Nicolas Jonckheere

doi:10.3390/ijms23062962

Abstract

Simple SummaryThe inositol-trisphosphate receptor (IP3R) is a key player in physiological and pathological intracellular calcium signaling. The objective of the present study was to assess the putative value of the three IP3R subtypes as prognostic biomarkers in breast cancer. We found that IP3R3 is the most strongly expressed subtype in breast cancer tissue. Furthermore, IP3R3 and IP3R1 are significantly more expressed in invasive breast cancer tissue than in non-tumor tissue. In contrast to IP3R1 and IP3R2, the expression of IP3R3 was positively correlated with prognostic factors including tumor size, regional node invasion, histologic grade, proliferation index, and hormonal status. By analyzing public databases, we found that the expression of all IP3R subtypes is significantly correlated with the overall survival and disease-free survival of patients with breast cancer. We conclude that relative to the other two IP3R subtypes, IP3R3 expression is upregulated in breast cancer and is correlated with prognostic factors. We strongly believe that our results will open up new perspectives with regard to the link between IP3Rs and breast cancer aggressiveness.Breast cancer is the leading cause of cancer death among women in worldwide and France. The disease prognosis and treatment differ from one breast cancer subtype to another, and the disease outcome depends on many prognostic factors. Deregulation of ion flux (especially Ca2+ flux) is involved in many pathophysiology processes, including carcinogenesis. Inside the cell, the inositol-trisphosphate receptor (IP3R) is a major player in the regulation of the Ca2+ flux from the endoplasmic reticulum to the cytoplasm. The IP3Rs (and particularly the IP3R3 subtype) are known to be involved in proliferation, migration, and invasion processes in breast cancer cell lines. The objective of the present study was to evaluate the potential value of IP3Rs as prognostic biomarkers in breast cancer. We found that expression levels of IP3R3 and IP3R1 (but not IP3R2) were significantly higher in invasive breast cancer of no special type than in non-tumor tissue from the same patient. However, the IP3R3 subtype was expressed more strongly than the IP3R1 and IP3R2 subtypes. Furthermore, the expression of IP3R3 (but not of IP3R1 or IP3R2) was positively correlated with prognostic factors such as tumor size, regional node invasion, histologic grade, proliferation index, and hormone receptor status. In an analysis of public databases, we found that all IP3Rs types are significantly associated with overall survival and progression-free survival in patients with breast cancer. We conclude that relative to the other two IP3R subtypes, IP3R3 expression is upregulated in breast cancer and is correlated with prognostic factors.

Highlights

In 2020, around 2.2 million new cases of breast cancer (BC) were diagnosed worldwide [1]—making this disease a major public health problem that affects 1 in 9 women at some point in life
We used Western blotting to evaluate the expression of each IP3 receptor (IP3R) subtype in Invasive breast carcinoma of no special type (IBC-NST) samples and non-tumor tissue samples. We found that both IP3R1 and IP3R3 expression were significantly higher in BC tissue than in non-tumor tissue (IP3R1; 1.59 ± 0.04 (N = 26) vs. 1 ± 0.03 (N = 12), respectively; p = 0.02; IP3R3: 3.37 ± 0.14 (N = 29) vs. 1 ± 0.02 (N = 12), respectively; p < 0.0001) (Figure 1A)
We evaluated the association between IP3RS expression and disease-free survival (Table 3); data were available for the “Breast cancer recurrence data, 9 datasets from 7 authors” and “Breast cancer Meta-base: 10 cohorts 22K gene” databases, comprising a total of 3449 samples

Summary

Introduction

In 2020, around 2.2 million new cases of breast cancer (BC) were diagnosed worldwide [1]—making this disease a major public health problem that affects 1 in 9 women at some point in life. The implementation of BC screening programs and the development of systemic treatments have reduced mortality and the incidence of metastatic cancer. Invasive breast carcinoma of no special type (IBC-NST) is the most frequent histologic subtype. Many prognostic criteria are applied when choosing an adjuvant treatment in BC; these criteria are variously clinical (tumor size, axillary lymph node invasion, remote metastases, etc.) and histologic (the Scarff-Bloom-Richardson (SBR) grade, hormone receptor (HmR) status, human epidermal growth factor 2 (HER2) expression, and the Ki67 index) [4–11]. Disease-free survival rates are higher for metastatic luminal BC than for metastatic HER2 or TN BCs [13]

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Conclusion