Sumoylation Pathway Is Required to Maintain the Basal Breast Cancer Subtype

Bogachek, Maria V.; Chen, Yizhen; Kulak, Mikhail V.; Woodfield, George W.; Cyr, Anthony R.; Park, Jung Min; Spanheimer, Philip M.; Li, Yingyue; Li, Tiandao; Weigel, Ronald J.

doi:10.1016/j.ccr.2014.04.008

Cited by 76 publications

(103 citation statements)

References 68 publications

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“…Overexpression of Tfap2a and Tfap2c mimics the mammary phenotype of RANK null mice (5,45,46). Tfap2a and Tfap2c maintain the luminal phenotype (28,29) and negatively regulate cancer stem cell markers (28). Although little is known about TFAP2B in mammary epithelia, our results suggest that, similarly to other members of the family, TFAP2B promotes luminal differentiation and is associated with good prognosis.…”

Section: Discussionmentioning

confidence: 55%

“…The AP2 transcription factor family is a set of retinoic acid inducible genes that governs the luminal epithelial phenotype in mammary development and carcinogenesis (28,29) and whose expression is associated with survival (30,31). Consistent with a tumor cell-luminal differentiation phenotype, GSEA analyses of the genes that characterize mammary differentiation hierarchy (20), revealed that the mature luminal upregulated set and the MaSC downregulated set, were overexpressed on the RANK-Fc-treated tumors (Fig.…”

Section: Rankl Negatively Regulates the Ap2 Transcription Factors Drmentioning

confidence: 84%

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RANK Signaling Blockade Reduces Breast Cancer Recurrence by Inducing Tumor Cell Differentiation

et al. 2016

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RANK expression is associated with poor prognosis in breast cancer even though its therapeutic potential remains unknown. RANKL and its receptor RANK are downstream effectors of the progesterone signaling pathway. However, RANK expression is enriched in hormone receptor negative adenocarcinomas, suggesting additional roles for RANK signaling beyond its hormonedependent function. Here, to explore the role of RANK signaling once tumors have developed, we use the mouse mammary tumor virus-Polyoma Middle T (MMTV-PyMT), which mimics RANK and RANKL expression patterns seen in human breast adenocarcinomas. Complementary genetic and pharmacologic approaches demonstrate that therapeutic inhibition of RANK signaling drastically reduces the cancer stem cell pool, decreases tumor and metastasis initiation, and enhances sensitivity to chemotherapy. Mechanistically, genome-wide expression analyses show that anti-RANKL therapy promotes lactogenic differentiation of tumor cells. Moreover, RANK signaling in tumor cells negatively regulates the expression of Ap2 transcription factors, and enhances the Wnt agonist Rspo1 and the Sca1-population, enriched in tumor-initiating cells. In addition, we found that expression of TFAP2B and the RANK inhibitor, OPG, in human breast cancer correlate and are associated with relapse-free tumors. These results support the use of RANKL inhibitors to reduce recurrence and metastasis in breast cancer patients based on its ability to induce tumor cell differentiation. Cancer Res; 76(19); 5857-69. Ó2016 AACR.

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Section: Discussionmentioning

confidence: 55%

Section: Rankl Negatively Regulates the Ap2 Transcription Factors Drmentioning

confidence: 84%

RANK Signaling Blockade Reduces Breast Cancer Recurrence by Inducing Tumor Cell Differentiation

et al. 2016

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“…SUMOylation occurs in a highly dynamic manner in the cell and substrate proteins can be modified with either mono-or poly-SUMOylation. The SUMO pathway plays a critical role in cellular stress response, such as DNA damage, genomic stability, and heat shock (10)(11)(12), and it has also been recently implicated in prostate and breast cancer (13)(14)(15)(16). However, the role of this pathway in KRAS mutant cancers is not clear.…”

mentioning

confidence: 99%

Oncogenesis driven by the Ras/Raf pathway requires the SUMO E2 ligase Ubc9

Swatkoski

Holly

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The small GTPase KRAS is frequently mutated in human cancer and currently there are no targeted therapies for KRAS mutant tumors. Here, we show that the small ubiquitin-like modifier (SUMO) pathway is required for KRAS-driven transformation. RNAi depletion of the SUMO E2 ligase Ubc9 suppresses 3D growth of KRAS mutant colorectal cancer cells in vitro and attenuates tumor growth in vivo. In KRAS mutant cells, a subset of proteins exhibit elevated levels of SUMOylation. Among these proteins, KAP1, CHD1, and EIF3L collectively support anchorage-independent growth, and the SUMOylation of KAP1 is necessary for its activity in this context. Thus, the SUMO pathway critically contributes to the transformed phenotype of KRAS mutant cells and Ubc9 presents a potential target for the treatment of KRAS mutant colorectal cancer.he Ras family of small GTPases are signal transduction molecules downstream of growth factor receptors. Ras activates a number of downstream effector pathways to regulate cell proliferation, survival and motility, these effectors include the MAP kinase (MAPK) pathway, the PI3-kinase (PI3K) pathway, the small GTPases RalA, RalB, and Rho, and phospholipase-Ce (1). Activating mutations in Ras are frequently found in human malignancies, with mutations in the KRAS gene being particularly prevalent. KRAS mutations occur in ∼60% of pancreatic ductal carcinomas, 26% of lung adenocarcinomas, and 45% of colorectal carcinomas, as well as a significant fraction of ovarian, endometrial, and biliary track cancers (2, 3). A salient hallmark of the Ras oncogene is its ability to transform cells to enable anchorage-independent 3D colony growth in vitro and tumor growth in vivo. Consequently, Ras mutant cancer cells often exhibit oncogene addiction to Ras such that extinction of the Ras oncogene leads to either a reversion of the transformed phenotype or loss of viability (4, 5). Therapeutically, the Ras oncoprotein has proven pharmacologically intractable thus far: intensive drug screening efforts have not yielded high-affinity, selective Ras inhibitors. Farnesyltransferase inhibitors that aimed to block Ras membrane localization are ineffective against KRAS because of its alternative geranylgeranylation. Inhibitors targeting Ras effector kinases, including MEK, PI3K, and Akt, are currently undergoing clinical evaluations, but they have yet to demonstrate clear clinical benefits (6). Thus, KRAS mutant tumors represent a class of "recalcitrant cancer" with urgent, unmet therapeutic needs.To gain new insight into the genetic dependencies of Ras mutant cancers and discover new therapeutic targets, we and others have previously carried out genome-wide synthetic lethal screens in KRAS mutant and WT cells to identify genes whose depletion leads to greater toxicity in KRAS mutant cells. In our screen we found a wide array of genes, many of which are involved in cellular stress response, that are required to maintain the viability of KRAS mutant cells (7). We proposed the concept of "nononcogene addiction" to explain the heig...

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“…The findings presented in Bogachek et al 9 offer a novel approach to the treatment of basal breast cancer and potentially other carcinomas in which the CD44 C/hi / CD24 ¡/low CSC population may be abrogated through inhibition of the SUMO pathway. Whereas conventional chemotherapy may preferentially eradicate the more differentiated tumor bulk, the addition of SUMO inhibitors may specifically target the CSC population, resulting in a more durable therapeutic response.…”

Section: Regulation Of Cancer Stem Cells By Sumoylationmentioning

confidence: 98%

“…One of the molecular characteristics of basal cancer is relatively high expression of CD44, a key marker of the CSC population, and TFAP2C has been shown to repress CD44 expression. 9 On the other hand, the highly homologous AP-2 family member TFAP2A lacks functional effects on luminal patterning. The molecular basis for functional specificity of the AP-2 family members depends upon sumoylation.…”

Section: Regulation Of Cancer Stem Cells By Sumoylationmentioning

confidence: 99%