Dual Src Kinase/Pretubulin Inhibitor KX-01, Sensitizes ER{alpha}-negative Breast Cancers to Tamoxifen through ER{alpha} Reexpression

Unlike breast cancer that is positive for estrogen receptor-α (ERα), there are no targeted therapies for triple-negative breast cancer (TNBC). ERα is silenced in TNBC through epigenetic changes including DNA methylation and histone acetylation. Restoring ERα expression in TNBC may sensitize patients to endocrine therapy. Expression of c-Src and ERα are inversely correlated in breast cancer suggesting that c-Src inhibition may lead to reexpression of ERα in TNBC. KX-01 is a peptide substrate–targeted Src/pretubulin inhibitor in clinical trials for solid tumors. KX-01 (1 mg/kg body weight-twice daily) inhibited growth of tamoxifen-resistant MDA-MB-231 and MDA-MB-157 TNBC xenografts in nude mice that was correlated with Src kinase inhibition. KX-01 also increased ERα mRNA and protein, as well as increased the ERα targets progesterone receptor (PR), pS2 (TFF1), cyclin D1 (CCND1), and c-myc (MYC) in MDA-MB-231 and MDA-MB-468, but not MDA-MB-157 xenografts. MDA-MB-231 and MDA-MB-468 tumors exhibited reduction in mesenchymal markers (vimentin, β-catenin) and increase in epithelial marker (E-cadherin) suggesting mesenchymal-to-epithelial transition (MET). KX-01 sensitized MDA-MB-231 and MDA-MB-468 tumors to tamoxifen growth inhibition and tamoxifen repression of the ERα targets pS2, cyclin D1, and c-myc. Chromatin immunoprecipitation (ChIP) of the ERα promoter in KX-01–treated tumors demonstrated enrichment ...
Source: Molecular Cancer Research - Category: Cancer & Oncology Authors: Tags: Chromatin, Epigenetics, and RNA Regulation Source Type: research

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In conclusion, PLB exerted anti-cancer activity and eliminated stem-like properties by attenuating Wnt/β-catenin signaling and FGF2 expression. These findings suggest that PLB could be a promising agent to treat endocrine resistant breast cancer.Graphical abstract
Source: Pharmacological Research - Category: Drugs & Pharmacology Source Type: research
Publication date: Available online 13 July 2019Source: Seminars in Cancer BiologyAuthor(s): Zoi Piperigkou, Nikos K. KaramanosAbstractThe biological functions of estrogens are regulated by estrogen receptors (ERα and ERβ), which contribute in the progression of several hormone-responsive cancer types via estrogen signaling mechanisms. The coordinated actions of ERs and extracellular matrix (ECM) macromolecules are principal mediators of ECM remodeling in the tumor and the adjacent stroma. In breast cancer, ERs are critical biomarkers as their expression in breast tumor determines the disease-free survival, yet g...
Source: Seminars in Cancer Biology - Category: Cancer & Oncology Source Type: research
Conclusion: The RSS is comparable to the AJCC8 PS for a patient population receiving chemotherapy as well as endocrine- and HER2-targeted therapy and further stratifies stage IV patients. PMID: 31281728 [PubMed]
Source: Journal of Breast Cancer - Category: Cancer & Oncology Tags: J Breast Cancer Source Type: research
In conclusion, e-As4S4 holds great potential for an alternative therapeutics in the treatment of breast cancer, due to its unique function of correcting the aggressive microenvironment. Introduction Metastasis is the leading cause of breast cancer mortality, which has been one major challenge in clinical treatment (1). In particular, triple-negative breast cancer (TNBC) is characterized by the absence of estrogen receptors (ER), progesterone receptors (PR) and HER2 receptors, which is one of the most aggressive types of breast cancers, marked by high rates of relapse, visceral metastases and early death (2, 3). The...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
In conclusion, our WGCNA analysis identified candidate prognostic biomarkers for further basic and clinical researches. Introduction Breast cancer is a frequently diagnosed malignancy and the leading cause of cancer death among females around the world, accounting for 24% of cancer diagnoses and 15% of cancer deaths in females. According to Global Cancer Statistics 2018, there will be nearly 2.1 million new cases diagnosed globally, with ~62 thousand deaths. The incident rates of breast cancer increased in most developing countries during last decades, resulting from a combination of social and economic factors, incl...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
ConclusionThese data suggest a previously unrecognized role for SNAIL in ILC, substantiating a context-dependent behavior for this EMT-TF.
Source: Breast Cancer Research and Treatment - Category: Cancer & Oncology Source Type: research
ConclusionsThis study suggests that the ER S118P variant does not affect risk for breast cancer or hormone therapy resistance. Germline screening and modification of treatments for patients harboring this variant are likely not warranted.
Source: Breast Cancer Research and Treatment - Category: Cancer & Oncology Source Type: research
The androgen receptor (AR) is expressed in the majority of breast cancers and across the main breast cancer subtypes. Despite the high frequency of AR expression in breast cancer its appraisal remains controve...
Source: Journal of Translational Medicine - Category: Research Authors: Tags: Research Source Type: research
Conclusion: In endocrine therapy resistant breast cancer cells Fulvestrant is ineffective in decreasing ER α levels. Our data suggest that in the ETR cells,H19 expression acts as an ER modulator and that its levels and subsequently ER α levels can be substantially decreased by blocking Notch and c-MET receptor signaling. Consequently, treating ETR cells with these pharmacological inhibitors helps overcome resistance to Fulvestrant and Tamoxifen.Cell Physiol Biochem 2018;51:1518 –1532
Source: Cellular Physiology and Biochemistry - Category: Cytology Source Type: research
In this study the dynamics over time of the tumor cells circulating in peripheral blood of patients, circulating tumor cells/ circulating epithelial tumor cells (CTC/CETC), as the systemic part of the tumor were investigated in 36 patients with ER+ primary breast cancer. CTC/CETCs were monitored serially during and after endocrine therapy. After termination of endocrine therapy 12 patients showed an increase in CTC/CETCs, with 8 of 12 suffering relapse. No change or a reduction was observed in 24 patients, with 2 of 24 suffering relapse. Initial tumor size was marginally prognostic (p = 0.053) but not nodal status nor the ...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Article Source Type: research
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