Role of proliferation in HER2 status predicted response to doxorubicin

Campiglio, Manuela; Somenzi, Giulia; Olgiati, Clelia; Beretta, Giovanni Luca; Balsari, Andrea; Zaffaroni, Nadia; Valagussa, Pinuccia; Ménard, Sylvie

doi:10.1002/ijc.11113

Cited by 51 publications

(37 citation statements)

References 33 publications

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“…Notably, relatively high concentrations of CDDP and DOX were used in the present study; however, this is similar to previous studies, of which several also used longer treatment durations (22,25,(29)(30)(31)(32)(33)(34). Data from a previous study (11), in addition to titration data from the present study, provided the optimum conditions for the phosphorylation of ERK in addition to ErbB2/3.…”

Section: Discussionsupporting

confidence: 81%

Mechanisms for DNA‑damaging agent‑induced inactivation of ErbB2 and ErbB3 via the ERK and p38 signaling pathways

et al. 2017

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Abstract. Cisplatin (CDDP) and doxorubicin (DOX) are chemotherapeutic drugs that trigger apoptosis by inducing DNA-damage. A previous study using breast cancer cells demonstrated the negative feedback modulation of the epidermal growth factor receptor (EGFR) and receptor tyrosine-protein kinase erbB-2 (ErbB2) via extracellular signal-regulated kinase (ERK)-mediated phosphorylation of conserved Thr-669 and Thr-677 residues, respectively, in the juxtamembrane domain. In addition, CDDP has been identified to cause negative feedback inhibition of activated EGFR in lung cancer cells. In the present study, the role of phosphorylation in the feedback control of the ErbB2/ErbB3 heterodimer in human breast and gastric cancer cells was investigated. Phosphorylation of ErbB2 at Thr-677 was induced by CDDP and DOX, which in turn reduced tyrosine autophosphorylation of ErbB2 and ErbB3. Treatment with trametinib, a mitogen-activated protein kinase inhibitor that blocks ERK-mediated Thr-677 phosphorylation, and substitution of Thr-677 to alanine, blocked the feedback inhibition of ErbB2 and ErbB3. In addition, these agents caused the degradation of ErbB proteins through the activation of p38 mitogen-activated protein kinase (p38) and ERK. These results demonstrate that chemotherapeutic agents trigger ERK-and p38-mediated post-translational downregulation of ErbB receptors. IntroductionThe receptor tyrosine-protein kinase erbB (ErbB) family of receptor tyrosine kinases (RTKs) consists of four members, ErbB1 [also known as epidermal growth factor receptor (EGFR)/HER1], ErbB2 (also known as proto-oncogene Neu/HER2), ErbB3 (also termed HER3) and ErbB4 (also termed HER4) (1). Upon activation, ErbB family members form homodimers or heterodimers that serve important roles in biological processes associated with differentiation, proliferation and apoptosis, primarily through mitogen-activated protein kinase and the phosphoinositide-3 kinase/RAC-alpha serine/threonine-protein kinase signaling pathways (2-6). ErbB mutations are frequently identified in human cancer, leading to aberrant ErbB expression and subsequent survival signals (7). Therefore, drugs targeting the ErbB receptors have been a central focus of cancer research (8,9).RTKs are non-canonically regulated by phosphorylation at their serine and threonine residues. For example, extracellular signal-regulated kinase (ERK)-mediated phosphorylation of a conserved threonine in the juxtamembrane domain of EGFR (Thr-669) and ErbB2 (Thr-677) is a typical negative feedback mechanism of ErbB dimers (10,11). Tumor necrosis factor-α-induced and p38 mitogen-activated protein kinase (p38)-mediated phosphorylation of EGFR (Ser-1046/1047) at the C-terminal tail is associated endocytosis of the receptor. A previous study demonstrated that cisplatin (CDDP), a well known DNA-damaging agent, induces the non-canonical phosphorylation of EGFR proteins harboring an activating mutation in lung cancer cells, resulting in negative feedback inhibition and endocytosis (12).ErbB2, which has been demonstr...

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Section: Discussionsupporting

confidence: 81%

Mechanisms for DNA‑damaging agent‑induced inactivation of ErbB2 and ErbB3 via the ERK and p38 signaling pathways

et al. 2017

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“…Because doxorubicin sensitivity of HER2-positive breast carcinoma cells does not directly depend on the receptor molecule but instead on the higher proliferation of HER2-positive cells compared with negative cells (36), it is possible that in our xenotransplant model consisting in proliferating tumor cells, tumor-initiating cells also proliferate and thereby become sensitive to the drugs' action. Such a possibility would not be inconsistent with the recent findings (3,5) that breast cancers from patients who received neoadjuvant chemotherapy or mice genetically manipulated for developing mammary tumors are substantially enriched for self-renewing cells.…”

Section: Discussionmentioning

confidence: 99%

Tumor-Initiating Cells of HER2-Positive Carcinoma Cell Lines Express the Highest Oncoprotein Levels and Are Sensitive to Trastuzumab

Magnifico¹,

Albano²,

Campaner

et al. 2009

Clinical Cancer Research

238

201

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Purpose: The existence of tumor-initiating cells in breast cancer has profound implications for cancer therapy. In this study, we investigated the sensitivity of tumor-initiating cells isolated from human epidermal growth factor receptor type 2 (HER2)-overexpressing carcinoma cell lines to trastuzumab, a compound used for the targeted therapy of breast cancer. Experimental Design: Spheres were analyzed by indirect immunofluorescence for HER2 cell surface expression and by real-time PCR for HER2 mRNA expression in the presence or absence of the Notch1signaling inhibitor (GSI) or Notch1small interfering RNA. Xenografts of HER2-overexpressing breast tumor cells were treated with trastuzumab or doxorubicin. The sphere-forming efficiency (SFE) and serial transplantability of tumors were assessed. Results: In HER2-overexpressing carcinoma cell lines, cells with tumor-initiating cell properties presented increased HER2 levels compared with the bulk cell population without modification in HER2 gene amplification. HER2 levels were controlled by Notch1 signaling, as shown by the reduction of HER2 cell surface expression and lower SFE following g-secretase inhibition or Notch1 specific silencing. We also show that trastuzumab was able to effectively target tumor-initiating cells of HER2-positive carcinoma cell lines, as indicated by the significant decrease in SFE and the loss of serial transplantability, following treatment of HER2-overexpressing xenotransplants. Conclusions: Here, we provide evidence for the therapeutic efficacy of trastuzumab in debulking and in targeting tumor-initiating cells of HER2-overexpressing tumors. We also propose that Notch signaling regulates HER2 expression, thereby representing a critical survival pathway of tumor-initiating cells.

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“…However the underlying mechanisms by which a lack of ER sensitizes cells to chemotherapy cytotoxicity is not fully established. The proliferative activity is notoriously greater in ER -primary breast cancer than in ER+ breast cancer (Campiglio et al 2003) and this relationship could offer a possible explanation.…”

Section: Discussionmentioning

confidence: 99%

Cytotoxic and antiproliferative activity of the single agent epirubicin versus epirubicin plus tamoxifen as primary chemotherapy in human breast cancer: a single-institution phase III trial

Bottini

Berruti²,

Brizzi³

et al. 2005

Endocrine Related Cancer

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This study was designed to address whether simultaneous primary chemo-hormonal therapy provides additional activity compared with chemotherapy alone in breast cancer patients with operable or locally advanced disease. Between January 1997 and January 2002, 211 consecutive patients with T2-4, N0-1, M0 breast cancer were randomized to receive either epirubicin alone (EPI) or epirubicin plus tamoxifen (EPI-TAM). Ki67 expression was evaluated immunohistochemically in tumor specimens obtained before chemotherapy by incision biopsy and at definitive surgery. Tumor shrinkage of >50% was obtained in 76% of patients randomized in the EPI arm and 81.9% of patients randomized in the EPI-TAM arm (not significant). The corresponding rates of clinical and pathological complete response were 20.2 and 21.9% (not significant), and 4.8 and 6.7% (not significant), respectively. Pathologically complete response was more frequently observed in estrogen receptor (ER)-negative (ER -) tumors (P=0.04) and correlated with elevated baseline Ki67 expression (P<0.01). Both EPI and EPI-TAM treatments resulted in a significant reduction in Ki67 expression, either in overall patients (P=0.000) or in patients with ER+ breast cancer (P=0.000). The reduction in Ki67 immunostaining in the EPI-TAM arm was greater than in the EPI arm, leading to a lower Ki67 expression at post-operative residual histology (P=0.0041). The addition of tamoxifen to epirubicin chemotherapy did not improve the response rate but led to a significantly higher reduction in the Ki67 expression. Baseline elevated Ki67 expression and the ER -status were both associated with a greater chance of obtaining a pathological complete response at residual histology.

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Role of proliferation in HER2 status predicted response to doxorubicin

Cited by 51 publications

References 33 publications

Mechanisms for DNA‑damaging agent‑induced inactivation of ErbB2 and ErbB3 via the ERK and p38 signaling pathways

Mechanisms for DNA‑damaging agent‑induced inactivation of ErbB2 and ErbB3 via the ERK and p38 signaling pathways

Tumor-Initiating Cells of HER2-Positive Carcinoma Cell Lines Express the Highest Oncoprotein Levels and Are Sensitive to Trastuzumab

Cytotoxic and antiproliferative activity of the single agent epirubicin versus epirubicin plus tamoxifen as primary chemotherapy in human breast cancer: a single-institution phase III trial

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