Amplification of c-myc gene and overexpression of c-Myc protein in breast cancer and adjacent non-neoplastic tissue

Chrzan, P.; Skokowski, Jarosław; Karmolinski, Andrzej; Pawełczyk, Tadeusz

doi:10.1016/s0009-9120(01)00260-0

Cited by 55 publications

(52 citation statements)

References 25 publications

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“…protein overexpression in the epithelial component of breast cancer (6)(7)(8)(9)(22)(23)(24). However, we were unable to identify any correlation between MYC expression and axillary lymph node positivity in our series, confirming the results of previous studies (5,6,25).…”

Section: Clinicoc-myc (Cyt) C-myc (Nuc) Ki67 P-mtor P-akt Pathologicasupporting

confidence: 89%

MYC is expressed in the stromal and epithelial cells of primary breast carcinoma and paired nodal metastases

Mundim

Pasini

Brentani

et al. 2015

Molecular and Clinical Oncology

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Abstract. The MYC oncogene is directly involved in the proliferation, metabolism, progression and distant metastasis of breast cancer. Since metastatic spread to the lymph nodes is often the first indication of propensity for metastatic dissemination, the MYC status in nodal disease may represent a decision-making variable. However, the analysis of MYC expression in stromal cells, namely cancer-associated fibroblasts (CAFs), which are known to play a critical role in cancer progression, remains poorly reported. The aim of this study was to determine the expression of MYC and other markers, including estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), p53, Ki67, epidermal growth factor receptor (EGFR), phosphorylated AKT (p-AKT) and phospho-mammalian target of rapamycin (p-mTOR) by immunohistochemistry in representative samples from 80 patients with ductal infiltrative breast cancer and 43 paired compromised axillary lymph nodes allocated in tissue microarrays (TMAs). The epithelial and stromal components of primary tumors and respective lymph node metastases were separately analyzed. MYC expression (cytoplasmic and nuclear) was a frequent event in the epithelial and stromal components of the primary tumors. The epithelial cells in the nodal metastases exhibited a trend for decreased MYC expression compared to that in the primary tumors (P=0.08) but retained the original status of the primary tumors for all other markers. The stromal cells were uniformly negative for ER, PR, HER2, p53, Ki67 and EGFR. Comparison of the stromas of primary tumors and respective lymph node metastases revealed a reduced frequency of nuclear MYC in 15% of the cases (P=0.003), whereas p-mTOR followed a similar trend (P=0.09). Analyses of the possible correlations among markers revealed that epithelial nuclear MYC was associated with p53 (P=0.048). This is an original study demonstrating a significant proportion of MYC expression (nuclear or cytoplasmic), as well p-mTOR and p-AKT expression, in the epithelial and stromal components of either the primary tumor or the nodal metastases. CAFs expressing MYC may establish an angiogenic microenvironment supporting cancer survival and facilitating colonization at the nodal metastatic site.

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Section: Clinicoc-myc (Cyt) C-myc (Nuc) Ki67 P-mtor P-akt Pathologicasupporting

confidence: 89%

MYC is expressed in the stromal and epithelial cells of primary breast carcinoma and paired nodal metastases

Mundim

Pasini

Brentani

et al. 2015

Molecular and Clinical Oncology

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“…In analyses of oncogenic mechanisms in breast cancer, accumulation of the MYC protein has been observed in 46% of primary breast tumors (1,31). Many mechanisms have been proposed to explain the elevated levels of MYC protein in tumors.…”

Section: Discussionmentioning

confidence: 99%

“…Expression of MYC is regulated at multiple levels, including protein stability, which is increased in several cancer types (1,3,4). MYC stability is regulated in part by sequential and interdependent phosphorylation at two conserved residues, threonine 58 (T58) and serine 62 (S62) (5).…”

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confidence: 99%

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Targeting c-MYC by antagonizing PP2A inhibitors in breast cancer

Janghorban¹,

Farrell²,

Allen-Petersen³

et al. 2014

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

168

175

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The transcription factor c-MYC is stabilized and activated by phosphorylation at serine 62 (S62) in breast cancer. Protein phosphatase 2A (PP2A) is a critical negative regulator of c-MYC through its ability to dephosphorylate S62. By inactivating c-MYC and other key signaling pathways, PP2A plays an important tumor suppressor function. Two endogenous inhibitors of PP2A, I2PP2A, Inhibitor-2 of PP2A (SET oncoprotein) and cancerous inhibitor of PP2A (CIP2A), inactivate PP2A and are overexpressed in several tumor types. Here we show that SET is overexpressed in about 50-60% and CIP2A in about 90% of breast cancers. Knockdown of SET or CIP2A reduces the tumorigenic potential of breast cancer cell lines both in vitro and in vivo. Treatment of breast cancer cells in vitro or in vivo with OP449, a novel SET antagonist, also decreases the tumorigenic potential of breast cancer cells and induces apoptosis. We show that this is, at least in part, due to decreased S62 phosphorylation of c-MYC and reduced c-MYC activity and target gene expression. Because of the ubiquitous expression and tumor suppressor activity of PP2A in cells, as well as the critical role of c-MYC in human cancer, we propose that activation of PP2A (here accomplished through antagonizing endogenous inhibitors) could be a novel antitumor strategy to posttranslationally target c-MYC in breast cancer.breast cancer therapy | phosphatase activator T he c-MYC (MYC) oncoprotein is overexpressed in human breast cancer and this is associated with poor clinical outcome (1, 2). Expression of MYC is regulated at multiple levels, including protein stability, which is increased in several cancer types (1,3,4). MYC stability is regulated in part by sequential and interdependent phosphorylation at two conserved residues, threonine 58 (T58) and serine 62 (S62) (5). MYC is phosphorylated at S62 (pS62) through the mitogen-activated protein kinase (MAPK) pathway or cyclin-dependent kinase (CDK) activation in response to growth signals and this modification increases its stability and oncogenic activity (5-8). When growth signals cease, GSK3, in a manner dependent upon prior phosphorylation at S62, phosphorylates T58 (pT58) (5, 6). T58 phosphorylation facilitates protein phosphatase 2A (PP2A)-mediated dephosphorylation of pS62 and recruitment of the E3 ubiquitin ligase SCF Fbw7 to initiate proteasomal destruction of MYC (9, 10). This process is facilitated by AXIN1, which helps nucleate a destruction complex for MYC at target gene promoters (11, 12). Our previous work has shown that MYC stability is increased in breast cancers and that this correlates with high pS62-and low pT58-MYC (4).PP2A is a ubiquitously expressed, heterotrimeric serinethreonine (S/T) phosphatase that mediates 30-50% of cellular S/T phosphatase activity (13). Target specificity of PP2A is directed by a variable regulatory (B) subunit, and we have shown that B56α is the isoform that directs PP2A to MYC (9, 13). Human cell transformation requires inhibition of PP2A activity and, in an siRNA screen, B56α, ...

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“…c-MYC is a well-characterized ERα target gene that plays a critical role in the ability of estrogen to enhance the proliferation of breast cancer cells (Cheng et al, 2006). MYC protooncogene is shown frequently up-regulated expression in breast cancers (Chrzan et al, 2001). Knockdown of c-Myc expression by RNAi could significantly inhibit MCF-7 breast tumor cells growth both in vitro and in vivo (Wang et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Transcription Regulation Network Analysis of MCF7 Breast Cancer Cells Exposed to Estradiol

Lü²,

Liu³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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Amplification of c-myc gene and overexpression of c-Myc protein in breast cancer and adjacent non-neoplastic tissue

Cited by 55 publications

References 25 publications

MYC is expressed in the stromal and epithelial cells of primary breast carcinoma and paired nodal metastases

MYC is expressed in the stromal and epithelial cells of primary breast carcinoma and paired nodal metastases

Targeting c-MYC by antagonizing PP2A inhibitors in breast cancer

Transcription Regulation Network Analysis of MCF7 Breast Cancer Cells Exposed to Estradiol

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