ZBED2 expression enhances interferon signaling and predicts better survival of estrogen receptor-negative breast cancer patients.
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ABSTRACT:
SUBMITTER: Liu D
PROVIDER: S-EPMC9257990 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Estrogen receptor (ER)-negative breast cancer is heterogeneous, and the biology of this disease has remained poorly understood. Molecular apocrine is a subtype of ER-negative breast cancer that is characterized by the overexpression of steroid-response genes such as AR and a high rate of ErbB2 amplification. In this study, we have identified a positive feedback loop between the AR and extracellular signal-regulated kinase (ERK) signaling pathways in molecular apocrine breast cancer. In this process, AR regulates ERK phosphorylation and kinase activity. In addition, AR inhibition results in the down-regulation of ERK target proteins phospho-RSK1, phospho-Elk-1, and c-Fos using an in vivo molecular apocrine model. Furthermore, we show that AR-mediated induction of ERK requires ErbB2, and AR activity, in turn, regulates ErbB2 expression as an AR target gene. These findings suggest that ErbB2 is an upstream connector between the AR and ERK signaling pathways. Another feature of this feedback loop is an ERK-mediated regulation of AR. In this respect, the inhibition of ERK phosphorylation reduces AR expression and CREB1-mediated transcriptional regulation of AR acts as a downstream connector between the AR and ERK signaling pathways in molecular apocrine cells. Finally, we demonstrate that AR-positive staining is associated with the overexpression of ERK signaling targets phospho-Elk-1 and c-Fos in ER-negative breast tumors, which further supports a cross-regulation between the AR and ERK signaling pathways in molecular apocrine subtype. This study demonstrates an AR-ERK feedback loop in ER-negative breast cancer with significant biologic and therapeutic implications in this disease.
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Project description:One third of all breast cancers are estrogen receptor alpha (ERalpha) negative, carry a poor overall prognosis, and do not respond well to currently available endocrine therapies. New treatment strategies are therefore required. Loss of Wnt-5a has previously been correlated with loss of ERalpha in clinical breast cancer samples, and we sought to investigate this association further. Three breast cancer cell lines (MDA-MB-231, MDA-MB-468, and 4T1) lacking expression of ERalpha and Wnt-5a, and one breast cancer cell line (T47D) expressing both proteins were used in this study. Wnt-5a signaling was generated in ERalpha-negative cell lines via stimulation with either recombinant Wnt-5a protein or a Wnt-5a-derived hexapeptide (Foxy-5) possessing Wnt-5a signaling properties. ERalpha expression was restored at both mRNA and protein level, after treatment with recombinant Wnt-5a or Foxy-5. This restoration of expression occurred in parallel with a reduction in methylation of the ERalpha promoter. Up-regulated ERalpha could be activated, initiate transcription of progesterone receptor and pS2, and activate an estrogen response element reporter construct. Significantly, breast cancer cells re-expressing ERalpha responded to treatment with the selective estrogen receptor modulator tamoxifen, as measured by induction of apoptosis and cell growth inhibition. Finally, Foxy-5 also increased ERalpha expression in an in vivo model of ERalpha-negative breast cancer. This represents the first evidence that Wnt-5a signaling acts to re-establish ERalpha expression in ERalpha-negative breast cancer cells. Our data suggest that combinatorial therapy with Foxy-5 and tamoxifen should be considered as a future treatment possibility for ERalpha-negative breast cancer patients.
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Project description:Endocrine therapies for breast cancer that target the estrogen receptor (ER) are ineffective in the 25%-30% of cases that are ER negative (ER-). Androgen receptor (AR) is expressed in 60%-70% of breast tumors, independent of ER status. How androgens and AR regulate breast cancer growth remains largely unknown. We find that AR is enriched in ER- breast tumors that overexpress HER2. Through analysis of the AR cistrome and androgen-regulated gene expression in ER-/HER2+ breast cancers we find that AR mediates ligand-dependent activation of Wnt and HER2 signaling pathways through direct transcriptional induction of WNT7B and HER3. Specific targeting of AR, Wnt or HER2 signaling impairs androgen-stimulated tumor cell growth suggesting potential therapeutic approaches for ER-/HER2+ breast cancers.
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Project description:Molecular apocrine is a subtype of estrogen receptor-negative (ER.) breast cancer, which is characterized by a steroid-response gene signature that includes androgen receptor, FOXA1, and a high frequency of ErbB2 overexpression. In this study, we demonstrate that there is a strong association between the overexpression of FOXA1 and ErbB2 in ER- breast tumors. This has led us to identify a cross-regulation network between FOXA1 and ErbB2 signaling in ER- breast cancer. We present two mechanisms to explain the association between FOXA1 and ErbB2 overexpression in molecular apocrine cells. In one process, ErbB2 signaling genes CREB1 and c-Fos regulate FOXA1 transcription, and in another process, AP2? regulates the expression of both FOXA1 and ErbB2. Moreover, we demonstrate that FOXA1, in turn, regulates the transcription of ErbB2 signaling genes. This includes a core gene signature that is shared across two molecular apocrine cell lines. Importantly, the most upregulated (RELB) and downregulated (PAK1) genes in this signature are direct FOXA1 targets. Our data suggest that FOXA1 acts as a dual-function transcription factor and the repressive function of FOXA1 on RELB can be explained by the recruitment of its binding partner corepressor TLE3. It is notable that a group of FOXA1-regulated genes vary across molecular apocrine cell lines leading to the differences in the functional effects of FOXA1 on extracellular signal-regulated kinase phosphorylation and cell viability between these lines. This study demonstrates that there is a cross-regulation network between FOXA1 and ErbB2 signaling that connects FOXA1 to some of the key signaling pathways in ER-breast cancer.
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Project description:IntroductionLymphocyte infiltration (LI) is often seen in breast cancer but its importance remains controversial. A positive correlation of human epidermal growth factor receptor 2 (HER2) amplification and LI has been described, which was associated with a more favorable outcome. However, specific lymphocytes might also promote tumor progression by shifting the cytokine milieu in the tumor.MethodsAffymetrix HG-U133A microarray data of 1,781 primary breast cancer samples from 12 datasets were included. The correlation of immune system-related metagenes with different immune cells, clinical parameters, and survival was analyzed.ResultsA large cluster of nearly 600 genes with functions in immune cells was consistently obtained in all datasets. Seven robust metagenes from this cluster can act as surrogate markers for the amount of different immune cell types in the breast cancer sample. An IgG metagene as a marker for B cells had no significant prognostic value. In contrast, a strong positive prognostic value for the T-cell surrogate marker (lymphocyte-specific kinase (LCK) metagene) was observed among all estrogen receptor (ER)-negative tumors and those ER-positive tumors with a HER2 overexpression. Moreover ER-negative tumors with high expression of both IgG and LCK metagenes seem to respond better to neoadjuvant chemotherapy.ConclusionsPrecise definitions of the specific subtypes of immune cells in the tumor can be accomplished from microarray data. These surrogate markers define subgroups of tumors with different prognosis. Importantly, all known prognostic gene signatures uniformly assign poor prognosis to all ER-negative tumors. In contrast, the LCK metagene actually separates the ER-negative group into better or worse prognosis.
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Project description:Comparison between Estrogen receptor positive and Estrogen receptor negative breast cancer samples Keywords: breast cancer type comparison 152 unique breast cancer tissue sample are included in the analysis. The total mRNA has been labeled with Cy5 and then hybridized on a two color arrays against the stratagen Human common reference that was previously labelled with Cy3.
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Project description:Protein kinase C (PKC) signaling can be activated rapidly by 17?-estradiol (E(2)) via nontraditional signaling in ER?-positive MCF7 and ER?-negative HCC38 breast cancer cells and is associated with tumorigenicity. Additionally, E(2) has been shown to elicit anti-apoptotic effects in cancer cells counteracting pro-apoptotic effects of chemotherapeutics. Supporting evidence suggests the existence of a membrane-associated ER that differs from the traditional receptors, ER? and ER?. Our aim was to identify the ER responsible for rapid PKC activation and to evaluate downstream effects, such as proliferation, apoptosis, and metastasis. RT-PCR, Western blot, and immunofluorescence were used to determine the presence of ER splice variants in multiple cell lines. E(2) effects on PKC activity were measured with and without ER-blocking antibodies. Cell proliferation was determined by [(3)H]thymidine incorporation, and cell viability was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, (MTT) whereas apoptosis was determined by DNA fragmentation and TUNEL. Quantitative RT-PCR and sandwich ELISA were used to determine the effects on metastatic factors. The role of membrane-dependent signaling in cancer cell invasiveness was examined using an in vitro assay. The results indicate the presence of an ER? splice variant, ER?36, in ER?-positive MCF7 and ER?-negative HCC38 breast cancer cells, which localized to plasma membranes and rapidly activated PKC in response to E(2), leading to deleterious effects such as enhancement of proliferation, protection against apoptosis, and enhancement of metastatic factors. These findings propose ER?36 as a novel target for the development of therapies that can prevent progression of breast cancer in the primary tumor as well as during metastasis.
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