TRIM47 activates NF-κB signaling via PKC-ε/PKD3 stabilization and contributes to endocrine therapy resistance in breast cancer

Increasing attention has been paid to roles of tripartite motif–containing (TRIM) family proteins in cancer biology, often functioning as E3 ubiquitin ligases. In the present study, we focus on a contribution of TRIM47 to breast cancer biology, particularly to endocrine therapy resistance, which is a major clinical problem in breast cancer treatment. We performed immunohistochemical analysis of TRIM47 protein expression in 116 clinical samples of breast cancer patients with postoperative endocrine therapy using tamoxifen. Our clinicopathological study showed that higher immunoreactivity scores of TRIM47 were significantly associated with higher relapse rate of breast cancer patients (P = 0.012). As functional analyses, we manipulated TRIM47 expression in estrogen receptor–positive breast cancer cells MCF-7 and its 4-hydroxytamoxifen (OHT)-resistant derivative OHTR, which was established in a long-term culture with OHT. TRIM47 promoted both MCF-7 and OHTR cell proliferation. MCF-7 cells acquired tamoxifen resistance by overexpressing exogenous TRIM47. We found that TRIM47 enhances nuclear factor kappa-B (NF-κB) signaling, which further up-regulates TRIM47. We showed that protein kinase C epsilon (PKC-ε) and protein kinase D3 (PKD3), known as NF-κB–activating protein kinases, are directly associated with TRIM47 and stabilized in the presence of TRIM47. As an underlying mechanism, we showed TRIM47-dependent lysine 27–linked polyubiquitination of PKC-ε. These results indicate that TRIM47 facilitates breast cancer proliferation and endocrine therapy resistance by forming a ternary complex with PKC-ε and PKD3. TRIM47 and its associated kinases can be a potential diagnostic and therapeutic target for breast cancer refractory to endocrine therapy.

Mitochondrial Fission Regulator 2 (MTFR2) Confers anti-ER Endocrine Therapy Resistance to Breast Cancer Cells by Modulating Mitochondrial Autophagy through Direct Phosphorylation of FUNDC1

Background: Mitochondrial fission regulator 2 (MTFR2) belongs to the MTFR1/ family with sequence similarity 54 (FAM54) family. Recently, it was reported that MTFR2 promotes the proliferation and invasion of breast cancers (BCs). However, the relationship between MTFR2 and endocrine crine therapy resistance is still unknown.Materials and methods: We collected 36 ER+ BC tissues and adjacent normal tissues and 10 samples from patients who received endocrine therapy. We detected the expression pattern of MTFR2 and the fold change in MTFR2 in cells treated with tamoxifen and letrozole. The autophagy status was also determined.Results: MTFR2 expression was upregulated in ER+ BC tissues and was strongly upregulated in the samples that were treated with endocrine therapy. Knocking out MTFR2 increased BC cell sensitivity to endocrine therapy. In addition, MTFR2 directly bound to FUNDC1 and promoted FUNDC1 phosphorylation, thus inhibiting autophagy.Conclusion: Taken together, our results indicate that increased expression of MTFR2 is associated with endocrine therapy resistance in BC cells. Our findings indicate that MTFR2 could serve as a novel therapeutic target for ER+ BC patients who suffer from endocrine therapy resistance.

Sodium/glucose cotransporter 1-dependent metabolic alterations induce tamoxifen resistance in breast cancer by promoting macrophage M2 polarization

Endocrine therapy is the standard treatment for estrogen receptor (ER)-positive breast cancer, but tumors eventually develop resistance. However, endocrine therapy resistance mechanisms mediated through interactions between breast cancer cells and tumor-associated macrophages (TAMs) are still unclear. Here, we characterized sodium/glucose cotransporter 1 (SGLT1) overexpression drives the highly glycolytic phenotype of tamoxifen-resistant breast cancer cells where enhanced lactic acid secretion promotes M2-like TAM polarization via the hypoxia-inducible factor-1α/signal transducer and activator of transcription-3 pathway. In turn, M2-like TAMs activate breast cancer cells through EGFR/PI3K/Akt signaling, providing feedback to upregulate SGLT1 and promote tamoxifen resistance and accelerate tumor growth in vitro and in vivo. Higher expression of SGLT1 and CD163+ TAMs was associated with endocrine-resistant ER-positive breast cancers. Our study identifies a novel vicious cycle of metabolic reprogramming, M2-like TAM polarization, and endocrine therapy resistance, which involves SGLT1, proposing SGLT1 as a therapeutic target to overcome endocrine therapy resistance in breast cancer.

Еstrogen receptor α (ESR1) and SRC family kinase (LYN) gene's mutations associated with ovarian cancer endocrine therapy resistance

Recently multiple data accumulated concerning mutations in the ESR1 gene coding estrogen receptor α (mutESR1) and in the LYN gene coding non receptor tyrosine kinase SRC family member (mutLYN) that are associated with endocrine therapy resistance and that could be considered as markers of endocrine therapy efficiency. In case of gynecologic cancers including ovarian cancer the most frequent mutESR1 are ESR1L536H/P/R/V , ESR1Y537S/N/C/H, ESR1D538G that emerge in the course of hormonotherapy especially using aromatase inhibitors. mutLYN including LYNE159K, LYND189Y, LYNK209N, LYNA370T, LYNG418R, LYNA503D are also identified. mutESR1 and mutLYN increase transcriptional activity of estrogen receptor α (ERα) coded with ESR1 gene and catalytic activity of LYN kinase inducing endocrine therapy resistance. Interdependence of ESR1 and LYN genes is revealed at the level of proteins that they code as the kinases of the SRC family including LYN activate ERα-dependent transcription due to the phosphorylation of ERα at Y537 amino-acid residue that is the most frequently mutated in tumors with endocrine therapy resistance. The aim of the review is revealing the clinical correlations of mutESR1 and mutLYN with the ovarian cancer endocrine therapy resistance that opens perspectives of mutESR1 and mutLYN use as new predictive markers of ovarian cancer and development of more efficient anti-tumor medicaments. In the review the information obtained from PubMed database for the last 20 years using the following key words: ESR1, LYN, mutation(s), estrogen receptor α (ERα), LYN kinase, SRC family kinases, ovarian cancer, gynecologic(al) cancer is discussed.