Intratumoral Expression Level of Epidermal Growth Factor Receptor and Cytokeratin 5/6 Is Significantly Associated With Nodal and Distant Metastases in Patients With Basal-like Triple-Negative Breast Carcinoma

Sutton, Lisa; Han, Jeong Soon; Molberg, Kyle; Sarode, Venetia; Cao, Dengfeng; Rakheja, Dinesh; Sailors, Joseph L.; Peng, Yan

doi:10.1309/ajcprmd3aruo5wpn

Cited by 53 publications

(44 citation statements)

References 22 publications

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“…Distant metastases typically occur early in the disease course, with a propensity for visceral metastasis to the lung and brain, rather than the lymph nodes, bone, or liver as seen in non-TNBCs. 30,[32][33][34] The development of targeted therapies is crucial to improve the clinical outcome for these patients. There is a need to further elucidate the molecular basis of TNBC to identify novel prognostic and predictive tumor biomarkers.…”

Section: Distinguishing Between Papillary Lesionsmentioning

confidence: 99%

“…49,50 Although not highly specific and/or sensitive, CK5/6 is expressed in 62.3% (43 of 69) of basal-like TNBCs, and EGFR is expressed in 91.3% (63 of the 69), making these 2 markers helpful when attempting to make a diagnosis of metastatic basal-like TNBC in the appropriate clinical setting. 34 Historically, CK5/6 is the most commonly used basal cytokeratin in determining the basal-like phenotype of TNBC. However, a study 4 reported CK5 positivity in 32 of 33 (97%) of basal-like TNBC tumors and suggested that CK5 is more sensitive than CK5/6 in identifying basal-like TN tumors.…”

Section: Potential Diagnostic Utility Of Basal Cytokeratins and Egfr mentioning

confidence: 99%

“…30,47,51,52 A group of researchers 34 reported that approximately one-third of basal-like TNBCs developed distant metastasis. They found that TNBCs with metastases had significantly higher expression of CK5/6 and EGFR than cases without metastases had.…”

Section: Potential Prognostic and Predictive Values Of Basal Cytokeramentioning

confidence: 99%

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Update on Immunohistochemical Analysis in Breast Lesions

Peng¹,

Butt²,

Chen³

et al. 2017

Archives of Pathology &Amp; Laboratory Medicine

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Context.-The utility of immunohistochemistry (IHC) in breast lesions needs to be updated with exceptions among these lesions. Biomarker studies with IHC in triple-negative breast carcinoma may help develop targeted therapies for this aggressive breast cancer. The distinction of metastatic lung adenocarcinoma to the breast and invasive breast carcinoma has significant prognostic and therapeutic implications. The determination can be challenging because both primary tumors can express estrogen receptor and/or HER2 by IHC, creating a diagnostic dilemma.Objectives.-To provide a practical update on the use of IHC markers in differential diagnoses in breast lesions, including benign, atypical, precancerous, and malignant tumors; to highlight recently published research findings on novel IHC markers in triple-negative breast carcinoma cases; and to reinforce the importance of IHC use as an ancillary tool in distinguishing metastatic lung adenocarcinoma to the breast from primary breast carcinoma using real case examples.Data Sources.-PubMed (US National Library of Medicine, Bethesda, Maryland) literature review and authors' research data and personal experiences were used in this review.Conclusions.-Immunohistochemistry has an important role in making differential diagnoses in breast lesions in morphologically equivocal settings; recognizing IHC expression status in the exceptions among these lesions will aid in the correct diagnosis of challenging breast cases. Studies suggest that androgen receptor, p16, p53, GATA3, and PELP1 may have potential diagnostic, prognostic, and predictive value in triple-negative breast carcinoma cases; these findings may provide insight and a greater understanding of the tumor biology in triple-negative breast carcinomas. In distinguishing metastatic estrogen receptor-positive or HER2 þ lung adenocarcinoma to the breast from primary breast carcinoma, napsin A, TTF-1, and GATA3 comprise a useful IHC panel.

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Section: Distinguishing Between Papillary Lesionsmentioning

confidence: 99%

Section: Potential Diagnostic Utility Of Basal Cytokeratins and Egfr mentioning

confidence: 99%

See 1 more Smart Citation

Update on Immunohistochemical Analysis in Breast Lesions

Peng¹,

Butt²,

Chen³

et al. 2017

Archives of Pathology &Amp; Laboratory Medicine

Self Cite

View full text Add to dashboard Cite

show abstract

“…MAPK and PI3K-AKT signaling pathways were over-activated, suggesting that TNBC cell growth depends on the EGFR signaling pathway (20). High intratumoral EGFR and CK5/6 expression levels may have a role in the development of nodal or distant metastases in TNBC and may be predictive of metastatic disease (21). An EGFR inhibitor has been reported to induce a change from the mesenchymal to the epithelial phenotype in TNBC cells; the EGFR tyrosine kinase inhibitor erlotinib inhibited tumor growth and metastasis in a SUM149 xenograft mouse model (22).…”

Section: Discussionmentioning

confidence: 99%

Curcumin induces apoptosis of triple-negative breast cancer cells by inhibition of EGFR expression

Sun

Liu

Huang

2012

Molecular Medicine Reports

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Abstract. Curcumin is the major component of the spice turmeric, extracted from the rhizomes of the plant Curcuma longa. It exerts a number of therapeutic effects, including the inhibition of cancer cell proliferation. However, the anti-carcinogenic mechanism of curcumin has not been fully elucidated. Triple-negative breast cancer (TNBC), which lacks expression of the estrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor 2 (HER2/EGFR2), is an aggressive breast cancer phenotype with a poor prognosis. In this study, we investigated the effects of curcumin on triple-negative breast cancer cells and the possible molecular mechanisms. The MDA-MB-231 TNBC cells were treated with curcumin, the growth inhibition ratio of the cells was measured by MTT assay, apoptosis was detected by flow cytometry and the expression levels of extracellular regulated protein kinase (ERK1/2), pERK1/2, EGFR and pEGFR were detected by western blotting. After treatment with different concentrations of curcumin, the growth inhibition rates of the MDA-MB-231 breast cancer cells of the 30 µmol/ml curcumin-treated group were significantly different from those of the other groups. The level of apoptosis of the curcumin-treated group (26.34%) was significantly different from that of the control group (2.76%). The expression levels of pERK1/2 and pEGFR in the curcumin-treated group were significantly decreased compared with those of the control group. These results indicate that curcumin is able to inhibit the proliferation of TNBC cells. Inhibition of the EGFR signaling pathway is the likely underlying molecular mechanism.

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“…TNBC patients with a basal-like classification have shorter disease-free or overall survival [202,203] and tumors from TNBC patients with metastatic disease exhibit higher levels of K5 and EFGR [204]. A potential influence of HIF-1α on the ability of the K5 and EGFR biomarkers to predict disease-free survival in basal-like TNBC is intriguing in light of our observations that, in cultured cells, EGF stabilizes HIF-1α expression at normoxia and further potentiates hypoxia-inducible expression of HIF-1α.…”

Section: Discussionmentioning

confidence: 99%

Identification of Novel HIF1A Target Genes That Regulate Tumor Progression and Metastasis

Peacock¹

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DEDICATION ABSTRACTHypoxia is a hallmark of most solid tumors. In response to hypoxic stress tumor cells adapt by regulating survival, metabolism and angiogenesis. The heterodimeric Hypoxia-Inducible Factor (HIF) transcription factors are the master regulators of this response. HIFs play key roles in many critical aspects of cancer biology including angiogenesis, stem cell maintenance, metabolic reprogramming, invasion, metastasis and resistance to radiation therapy and chemotherapy. Overexpression of HIF-1α and HIF-2α has been documented in multiple human cancers and HIF-1α protein is over-expressed in ~30% of primary breast tumors and ~70% of metastases, which independently correlates with poor prognosis and decreased survival in patients. A precise role for HIF-2α in breast cancer is still being elucidated.Our lab has established primary mammary tumor epithelial cells (MTECs) from late stage carcinomas originating in PyMT+; Hif1a floxed mice. These MTECs were exposed to either Adenovirus-beta-gal or -Cre to create wild-type (WT) and knockout (KO) cells, respectively. Deletion of HIF-1 activity reduced primary tumor growth by ~60% and the formation of lung macrometastases originating from mammary fat pad tumors by >90%. In addition, deletion of Hif1a reduced mammary tumorsphere formation efficiency (TSE) in vitro and tumor initiating cell (TIC) frequency in vivo. In contrast, in triple negative models of breast cancer, knockdown of HIF1A had the opposite phenotype, increasing TSE in vitro and increased primary mammary tumor growth in vivo. ITGA6 (CD49f) was identified as one HIF-1α-dependent cancer stem cell marker that enriches for both primary mammary tumor growth and metastasis to the lung. Microarray profiling conducted to identify genes differentially expressed between PyMT WT and KO cells and end-stage WT and KO tumors revealed several genes that were down-regulated in both data sets in response to deletion of Hif1a. One mRNA of particular interest, creatine kinase brain isoform (Ckb) was down-regulated in KO cells >100 fold and >2 fold in end-stage tumors. Transplantation of Ckb knockdown (KD) PyMT cells to the mammary fat pad delayed initiation of palpable tumors by >30 days. When cells were introduced into the circulation via tail vein injection, 20% of mice injected with Ckb KD cells developed lung metastases whereas 100% of mice injected with WT cells developed metastases. Likewise, when mice injected with WT PyMT cells were treated daily with a CKB chemical inhibitor, cyclocreatine (cCr), lungs of vehicle treated (saline) mice were almost completely covered with surface metastases, while lungs of cCr treated mice contained very few metastases.Overall, our data show that HIF-1α strongly promotes mammary tumor initiation, progression and metastasis, in part through regulation of TIC activity. Metastasis is the major cause of mortality in breast cancer patients. Further characterization of the distinct roles of HIF-1α versus HIF-2α in breast cancer and metastasis, and genes downstream of the HIFs, suc...

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Intratumoral Expression Level of Epidermal Growth Factor Receptor and Cytokeratin 5/6 Is Significantly Associated With Nodal and Distant Metastases in Patients With Basal-like Triple-Negative Breast Carcinoma

Cited by 53 publications

References 22 publications

Update on Immunohistochemical Analysis in Breast Lesions

Update on Immunohistochemical Analysis in Breast Lesions

Curcumin induces apoptosis of triple-negative breast cancer cells by inhibition of EGFR expression

Identification of Novel HIF1A Target Genes That Regulate Tumor Progression and Metastasis

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