Cytoplasmic Colocalization of RXRα and PPARγ as an Independent Negative Prognosticator for Breast Cancer Patients

Abstract

Retinoid X receptor α (RXRα) is a nuclear receptor (NR) which functions as the primary heterodimeric partner of other NRs including the peroxisome proliferator-activated receptor γ (PPARγ). We previously reported that, in breast cancers (BC), the subcellular localization of these two receptors was strongly associated with patient prognosis. In the present work, we investigated the prognosis value of the combined cytoplasmic expression of RXRα and PPARγ using a retrospective cohort of 250 BC samples. Patients with tumors expressing both NRs in tumor cell cytoplasm exhibited a significant shorter overall (OS) and disease-free survival (DFS). This was also observed for patients with stage 1 tumors. Cox univariate analysis indicated that patients with tumors coexpressing RXRα and PPARγ in the cytoplasm of tumor cells have a decreased 5 y OS rate. Cytoplasmic co-expression of the two NRs significantly correlated with HER2 positivity and with NCAD and CD133, two markers of tumor aggressiveness. Finally, in Cox multivariate analysis, the co-expression of RXRα and PPARγ in the cytoplasm appeared as an independent OS prognosticator. Altogether, this study demonstrates that the cytoplasmic co-expression of RXRα and PPARγ could be of relevance for clinicians by identifying high-risk BC patients, especially amongst those with early and node-negative disease.

Protein Profiling of Breast Carcinomas Reveals Expression of Immune-Suppressive Factors and Signatures Relevant for Patient Outcome

“…Phosphorylated PPARγ (pS112) was present in higher amounts in samples with lower immune cell infiltration. Besides its common function in adipogenesis and lipid metabolism [ 68 ], PPARv has been linked to worse outcomes in breast cancer patients [ 69 , 70 ], as well as the evasion of immunosurveillance and the impairment of CD8 T-cell infiltration in muscle-invasive bladder cancer [ 71 ]. Our data suggest that higher PPARγ phosphorylation impairs immune cell infiltration in breast cancer, ultimately worsening patient outcomes.…”

Prognostic Relevance of Nuclear Receptors in Relation to Peritumoral Inflammation and Tumor Infiltration by Lymphocytes in Breast Cancer

“…In a recent study on the same patient cohort, we analyzed the combined cytoplasmic expression of RXRα and PPARγ. Patients with tumors expressing both NRs in the cytoplasm of tumor cells exhibited significantly shorter OS and DFS [ 39 ]. Based on those results, we investigated the correlation between TIL levels and the expression of nuclear type II receptors.…”

“…It is already known that the expression of PPARγ, as the key regulator of lipogenesis, is altered in breast cancer [ 60 ]. We could show very recently that cytoplasmic PPARγ is a negative prognosticator in breast cancer [ 35 , 39 ]. PPARγ can determine the cellular phenotype by regulating differentiation and function by activating the transcription of PPARγ target genes [ 61 ].…”

“…Using the above-described BC cohort, the expression of type I and type II nuclear receptors has been previously analyzed by immunohistochemistry by our group. Information was specifically evaluated regarding ERα and PR [ 34 ], PPARγ [ 35 ], thyroid hormone receptors (TRs) [ 36 , 37 ], AhR [ 33 ], LXR [ 38 ], and RXRα [ 39 , 40 ].…”

Retinoic Acid and Retinoid X Receptors

“…These findings provide the theoretical basis for the use of RAR agonists, and in particular of RARγ-specific agonists, in the treatment of heterotopic ossification, a pathological process defined by the formation of bone in soft tissues by recapitulating developmental skeletogenesis. The work by Shao and colleagues [ 32 ] focuses on the implication of RXR and another NR, the peroxisome proliferator-activated receptor (PPAR or NR1C), in breast cancer progression. Based on previous observations, they evaluate whether the cytoplasmic colocalization of RXRα and PPARγ can be used as a negative indicator for patient prognosis.…”