Chemical degrader enhances the treatment of androgen receptor-positive triple-negative breast cancer.

Androgen receptor (AR) is a promising therapeutic target for AR-positive triple-negative breast cancer (TNBC). However, clinical trials of AR inhibitors only reveal modest therapeutic efficacy for AR-positive TNBC, and drug resistance is also inevitable. To address these challenges, we herein report the use of an AR-targeting proteolysis targeting chimera (AR-PROTAC) to treat AR-positive TNBC. We demonstrated that AR-PROTAC potently degraded AR protein via the ubiquitin-proteasome pathway in AR-positive TNBC BT549 cells, with a half degradation concentration of ∼46.9 nM. By evaluating the therapeutic efficacies in vitro and in vivo, we validated that AR-PROTAC was superior to enzalutamide, an AR inhibitor. Specifically, AR-PROTAC at 100 nM reduced BT549 cell viability by up to ∼80%, and AR-PRTOAC at 10 mg/kg suppressed tumor growth by ∼60% when administrated intratumorally in subcutaneous BT549 tumor mice model. Overall, these results demonstrate for the first time that PROTAC holds promise to enhance the treatment of AR-positive TNBC.

Estrogen receptor (ER) was regulated by RNPC1 stabilizing mRNA in ER positive breast cancer.

Estrogen receptors (ERs), including ERα and ERß, mainly mediate the genotype effect of estrogen. ERα is highly expressed in most breast cancers. Endocrine therapy is the most effective and safety adjunctive therapy for ER positive breast cancers. RNPC1, an RNA binding protein (RBP), post-transcriptionally regulating gene expression, is emerging as a critical mechanism for gene regulation in mammalian cells. In this study, we revealed RNPC1's capability of regulating ERα expression. There was a significant correlation between RNPC1 and ERα expression in breast cancer tissues. Ectopic expression of RNPC1 could increase ERα transcript and expression in breast cancer cells, and vice versa. Consistent with this, RNPC1 was able to bind to ERα transcript to increase its stability. Furthermore, overexpression of ERα could decrease the level of RNPC1 transcript and protein. It suggested a novel mechanism by which ERα expression was regulated via stabilizing mRNA. A regulatory feedback loop between RNPC1 and ERα was proved. It indicated that RNPC1 played a crucial role in ERα regulation in ER-positive breast cancers via binding to ERα mRNA. These findings might provide new insights into breast cancer endocrine therapy and ERα research.

Up-regulation of S100A16 expression promotes epithelial-mesenchymal transition via Notch1 pathway in breast cancer.

BACKGROUND: Our previous studies demonstrated that S100A16 promotes adipogenesis and is involved in weight gain attenuation induced by dietary calcium. Till now, the function of S100A16 in the breast cancer remains to be elucidated. RESULTS: In this study, we observed that S100A16 was expressed in higher levels in human breast cancer tissues compared with paired adjacent non-cancerous tissues. Further examination showed that overexpression of S100A16 in MCF-7 cells could increase cell proliferation and colony formation. One major mechanistic change was that S100A16 was able to up-regulate the transcription factors Notch1, ZEB1, and ZEB2, which had the capacities to directly repress the expression of epithelial markers E-cadherin and ß-catenin but increase mesenchymal markers N-cadherin and vimentin, a characterized phenotype of epithelial-mensenchymal transition (EMT). In addition to display with morphologic change, migration and invasion were increased in S100A16 over-expressed MCF-7 cells. Importantly, knockdown of Notch1 by specific siRNA could reverse the EMT induced by S100A16 overexpression, which confirmed that Notch1 played a critical role in the process of EMT induced by S100A16. CONCLUSIONS: All together, our data indicated that S100A16 had a potential function to regulate some embryonic transcription factors to promote EMT in breast cancer cells which may be an important target site for the therapy of breast cancer.

RNA-binding protein RNPC1: acting as a tumor suppressor in breast cancer.

BACKGROUND: RNA binding proteins (RBPs) play a fundamental role in posttranscriptional control of gene expression. Different RBPs have oncogenic or tumor-suppressive functions on human cancers. RNPC1 belongs to the RNA recognition motif (RRM) family of RBPs, which could regulate expression of diverse targets by mRNA stability in human cancer cells. Several studies reported that RNPC1 played an important role in cancer, mostly acting as an oncogene or up-regulating in tumors. However, its role in human breast cancer remains unclear. METHODS: In the present study, we investigated the functional and mechanistic roles of RNPC1 in attenuating invasive signal including reverse epithelial-mesenchymal transition (EMT) to inhibit breast cancer cells aggressiveness in vitro. Moreover, RNPC1 suppress tumorigenicity in vivo. Further, we studied the expression of RNPC1 in breast cancer tissue and adjacent normal breast tissue by quantitative RT-PCR (qRT-PCR) and Western blot. RESULTS: We observed that RNPC1 expression was silenced in breast cancer cell lines compared to breast epithelial cells. More important, RNPC1 was frequently silenced in breast cancer tissue compared to adjacent normal breast tissue. Low RNPC1 mRNA expression was associated with higher clinical stages and mutp53, while low level of RNPC1 protein was associated with higher lymph node metastasis, mutp53 and lower progesterone receptor (PR). Functional assays showed ectopic expression of RNPC1 could inhibit breast tumor cell proliferation in vivo and in vitro through inducing cell cycle arrest, and further suppress tumor cell migration and invasion partly through repressing mutant p53 (mutp53) induced EMT. CONCLUSIONS: Overall, our findings indicated that RNPC1 had a potential function to play a tumor-suppressor role which may be a potential marker in the therapeutic and prognostic of breast cancer.

The anticancer effect and mechanism of α-hederin on breast cancer cells.

Natural plant products occupy a very important position in the area of cancer chemotherapy. Many triterpenoid saponins have been proved as potential agents for chemoprevention and therapy of breast cancer. α-hederin, a monodesmosidic triterpenoid saponin distributed in Hedera or Nigella species, displays many biological activities. It is increasingly investigated for its promising anticancer potential since it has been shown to have cytotoxicity against several types of cancer cells. However, studies of α-hederin on breast cancer are limited, most of which focus on biological activity, while the mechanisms have not been widely reported yet. Previously, we purified and identified α-hederin from Clematis ganpiniana, a herb used in traditional Chinese medicine with antitumor action. In the present study, α-hederin showed strong inhibitory activity on the growth of breast cancer cells and induced apoptosis in these cells. α-hederin induced depolarization of mitochondrial membrane potential which released Apaf-1 and cytochrome c from the intermembrane space into the cytosol, where they promoted caspase-3 and caspase-9 activation. This is the first report on the growth inhibition and pro-apoptotic effects of α-hederin on breast cancer cells and the relative apoptosis pathways. It implied that triterpenoid saponin α-hederin could be a promising candidate for chemotherapy of breast cancer.

The apoptotic effect of D Rhamnose ß-hederin, a novel oleanane-type triterpenoid saponin on breast cancer cells.

There is growing interest in development of natural products as anti-cancer and chemopreventive agents. Many triterpenoids have been proved as potential agents for chemoprevention and therapy of breast cancer. Ginsenosides from ginseng, which mostly belong to dammarane-type triterpenoids, have gained great attention for their anti-breast cancer activity with diverse mechanisms. However, studies of other kinds of triterpenoid saponins on breast cancer are limited. Previously, we purified and identified a novel oleanane-type triterpene saponin named D Rhamnose ß-hederin (DRß-H) from Clematis ganpiniana, a Chinese traditional anti-tumor herb. In the present study, DRß-H showed strong inhibitory activity on the growth of various breast cancer cells and induced apoptosis in these cells. DRß-H inhibited PI3K/AKT and activated ERK signaling pathway. PI3K inhibitor LY294002 synergistically enhanced DRß-H-induced apoptosis whereas MEK inhibitor U0126 reduced the apoptosis rate. Moreover, DRß-H regulated the ratio of pro-apoptotic and anti-apoptotic Bcl-2 family proteins. Furthermore, DRß-H induced depolarization of mitochondrial membrane potential which released Apaf-1 and Cytochrome C from the inter membrane space into the cytosol, where they promoted caspase-9 and caspase-3 activation. This is the first report on the pro-apoptotic effects of DRß-H, a novel oleanane-type triterpenoid saponin, on breast cancer cells and its comprehensive apoptosis pathways. It implied that oleanane-type triterpenoid saponin DRß-H could be a promising candidate for chemotherapy of breast cancer.

Family history and risk of ductal carcinoma in situ and triple negative breast cancer in a Han Chinese population: a case-control study.

BACKGROUND: The association between family history and risk of triple negative breast cancer and ductal carcinoma in situ (DCIS) has not been well investigated, especially in Asian populations. We investigated the association between family history and risk of DCIS or triple negative breast cancer in a Han Chinese population. METHODS: A case-control study, comprising 926 breast cancer patients and 1,187 benign breast disease controls, was conducted in our hospital. Multivariate logistic regression was used to assess the relationships between family history and risk of DCIS or triple negative breast cancer. RESULTS: Subjects with a family history of breast cancer had higher breast cancer risk than those without a family history (odds ratio (OR) = 2.11, 95% confidence interval (CI) = 1.26 to 3.52). Family history was not significantly associated with an increased risk of DCIS (OR = 1.27, 95% CI = 0.36 to 4.46), while family history was significantly associated with an increased risk of invasive breast cancer (OR = 2.22, 95% CI = 1.32 to 3.75), irrespective of triple negative breast cancer (OR = 3.35, 95% CI = 1.43 to 7.88) or non-triple negative breast cancer (OR = 2.14, 95% CI = 1.21 to 3.80). CONCLUSION: Our results indicate that having a family history of breast cancer is associated with an increased risk of triple negative breast cancer with a magnitude of association similar to that for non-triple negative breast cancer. Furthermore, family history is not significantly associated with an increased risk of DCIS. Future cohort studies with larger sample sizes are still needed to explore these relationships.

Low serum creatine kinase levels in breast cancer patients: a case-control study.

BACKGROUND: Previous studies provide an ambiguous picture of creatine kinase (CK) expression and activities in malignancy. The aim of this study was to investigate the role of serum CK level in breast cancer patients. PATIENTS AND METHODS: 823 female patients diagnosed with breast cancer were consecutively recruited as cases, and 823 age-match patients with benign breast disease were selected as controls. Serum CK was analyzed by commercially available standardized methods. RESULTS: Serum CK level was significantly associated with breast cancer (P = 0.005) and subtypes of breast cancer, including breast cancer with diameter>2 cm (P = 0.031) and stage IIIbreast cancer (P = 0.025). The mean serum CK level in patients with>2 cm tumor was significantly lower than that in≤2 cm (P = 0.0475), and the mean serum CK level of stage III breast cancer patients was significantly lower than that of stage I and II breast cancer patients (P = 0.0246). Furthermore, a significant difference (P = 0.004) was observed between serum CK level and ERBB2+breast cancer not other molecular subtypes. CONCLUSIONS: Serum CK levels in cases was significantly lower compared with controls. Notably, our results indicated for the first time that there was a negative correlation between serum CK levels and breast cancer stage. Serum CK level, which may reflect the status of host immunity, may be an important factor in determining breast cancer development and progression.