Basal-HER2 phenotype shows poorer survival than basal-like phenotype in hormone receptor-negative invasive breast cancers

Liu, Hui; Qiu, Fan; Zhang, Zhihong; Li, Xiao; Yu, Huan; Meng, F.

doi:10.1016/j.humpath.2007.06.012

Cited by 63 publications

(63 citation statements)

References 20 publications

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“…Our current confirmation of the presence of basal cytokeratins (i.e. CK5/CK6) in HER2 + breast carcinomas, thus denoting a basal/HER2 + phenotype that has been shown recently to exhibit poorer survival than basal-like phenotype in hormone receptor-negative invasive breast carcinomas (24), therefore raises the possibility that these tumors may originate from stem cells that subsequently undergo variable degrees of basal and luminal differentiation. Given that prognostic features of the basal/HER2 + phenotype might be intrinsically different to those found in either HER2 + or basal-like breast carcinomas, it would be reasonable to suggest that this group of tumors might require different treatment strategies.…”

Section: Discussionsupporting

confidence: 77%

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Pathway-focused proteomic signatures in HER2-overexpressing breast cancer with a basal-like phenotype: New insights into de novo resistance to trastuzumab (Herceptin)

et al. 2010

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Abstract.Pioneering clinical studies in de novo refractoriness to the anti-HER2 monoclonal antibody trastuzumab have suggested that HER2 gene-amplification can take place also in a basal-like molecular background to generate basal/HER2 + tumors intrinsically resistant to trastuzumab. Here, we first investigated the unique histogenesis of the basal/HER2 + phenotype in breast carcinomas. The presence of basal CK5/CK6 cytokeratin expression in HER2 + tumors revealed a significant overlap in the histological features of HER2 + /CK5/6 + and basal-like breast carcinomas. Basal/ HER2 + tumors were typically poorly differentiated, highgrade invasive ductal carcinomas with large geographic necrosis, pushing margins of invasion, syncytial arrangement of tumor cells, ribbon-or festoon-like architecture, squamous metaplasia, stromal lymphocytic infiltrates, high mitotic index and strong p53 positivity. Secondly, we performed low-scale proteomic approaches in JIMT-1 cells, a unique model of HER2-gene amplified trastuzumab-resistant breast carcinoma with a basal-like phenotype, to develop biomarker signatures that may differentiate trastuzumab-responsive from non-responsive tumors. When applying antibody-based array technology to the extracellular milieu of trastuzumabrefractory JIMT-1 and trastuzumab-sensitive SKBR3 cell cultures, JIMT-1 cells were found to secrete higher amounts of several growth factors including amphiregulin, EGF, IGFBP-6, PDGF-AA, neurotrophins, TGFß and VEGF. Semiquantitative signaling node multi-target sandwich ELISAs revealed that JIMT-1 cells drastically overactivate RelA, the prosurvival subunit of NF-κB as compared to trastuzumabsensitive luminal/HER2 + SKBR3 cells. When simultaneously assessing the activation status of 42 receptor tyrosine kinases (RTK) using a human phospho-RTK array, JIMT-1 cells were found to constitutively display hyperactivation of the insulin-like growth factor-I receptor (IGF-1R). High-content immunofluorescence imaging revealed that activated IGF-1R mainly localized at focal adhesion-like structures in JIMT-1 cells. In vitro wound healing assays suggested that this functional reorganization of the JIMT-1 cytoskeletal reorganization may account for an exacerbated trastuzumab-refractory 'migratogenic' phenotype. Forthcoming studies should validate the notion that identification of basal-like immunophenotypes and/or basal-like molecular signatures within HER2 + breast carcinomas may provide rapid means to define subgroups of breast cancer patients likely to display resistance to trastuzumab ab initio.

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Section: Discussionsupporting

confidence: 77%

“…CK5/CK6) (21,24). In some cases, HER2 + breast tumors that stained positively for basal cytokeratins displayed a focal checkerboard pattern with CK5/CK6-negative and CK5/CK6-positive tumor cells located next to each other (Fig.…”

Section: A Subgroup Of Her2-overexpressing Breast Carcinomas Overlapsmentioning

confidence: 99%

Pathway-focused proteomic signatures in HER2-overexpressing breast cancer with a basal-like phenotype: New insights into de novo resistance to trastuzumab (Herceptin)

et al. 2010

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“…HCC1954 cells are classified in the basal-like subtype of HER2-amplified breast cancer. Because this subtype has been associated with poor prognosis in the clinic (36) it is encouraging that GDC-0941 treatment as a single agent and in combination with trastuzumab and pertuzumab showed potent efficacy in 3D lrECM assays (Fig. 5C).…”

Section: Her3 Expression Was Determined Bymentioning

confidence: 98%

Suppression of HER2/HER3-Mediated Growth of Breast Cancer Cells with Combinations of GDC-0941 PI3K Inhibitor, Trastuzumab, and Pertuzumab

Yao¹,

Zhou²,

Lee-Hoeflich³

et al. 2009

Clinical Cancer Research

119

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Purpose: Oncogenic activation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway is prevalent in breast cancer and has been associated with resistance to HER2 inhibitors in the clinic.We therefore investigated the combinatorial activity of GDC-0941, a novel class IPI3K inhibitor, with standard-of-care therapies for HER2-amplified breast cancer. Experimental Design: Three-dimensional laminin-rich extracellular matrix cultures of human breast cancer cells were utilized to provide a physiologically relevant approach to analyze the efficacy and molecular mechanism of combination therapies ex vivo. Combination studies were done using GDC-0941 with trastuzumab (Herceptin), pertuzumab, lapatinib (Tykerb), and docetaxel, the principal therapeutic agents that are either approved or being evaluated for treatment of early HER2-positive breast cancer.Results: Significant GDC-0941 activity (EC 50 <1 Amol/L) was observed for >70% of breast cancer cell lines that were examined in three-dimensional laminin-rich extracellular matrix culture. Differential responsiveness to GDC-0941as a single agent was observed for luminal breast cancer cells upon stimulation with the HER3 ligand, heregulin. Combined treatment of GDC-0941, trastuzumab, and pertuzumab resulted in growth inhibition, altered acinar morphology, and suppression of AKT mitogen-activated protein kinase (MAPK) / extracellular signed-regulated kinase (ERK) kinase and MEK effector signaling pathways for HER2-amplified cells in both normal and heregulin-supplemented media. The GDC-0941 and lapatinib combination further showed that inhibition of HER2 activity was essential for maximum combinatorial efficacy. PI3K inhibition also rendered HER2-amplified BT-474M1cells and tumor xenografts more sensitive to docetaxel. Conclusions: GDC-0941 is efficacious in preclinical models of breast cancer. The addition of GDC-0941to HER2-directed treatment could augment clinical benefit in breast cancer patients.

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“…The luminal subtype expresses ER and PR, lacks HER2 amplification, and is associated with a better prognosis (34). About 50% of HER2-positive cancers are ER + , and there are reports that ER status is reflected in expression profiles resulting in HER2-basal and HER2-luminal groups, with HER2-basal exhibiting a worse prognosis (17,35). Interestingly, breast cancer cell lines classified as basal or HER2-basal exhibited lower levels of PPM1H than did the luminal counterparts (Fig.…”

Section: Research Articlementioning

confidence: 99%

PPM1H Is a p27 Phosphatase Implicated in Trastuzumab Resistance

et al. 2011

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The HER2 oncogene is overexpressed or amplified in 20% of breast cancers. HER2-positive cancer historically portends a poor prognosis, but the HER2-targeted therapy trastuzumab mitigates this otherwise ominous distinction. Nevertheless, some patients suffer disease recurrence despite trastuzumab, and metastatic disease remains largely incurable due to innate and acquired resistance. Thus, understanding trastuzumab resistance remains an unmet medical need. Through RNA interference screening, we discovered that knockdown of the serine/threonine phosphatase PPM1H confers trastuzumab resistance via reduction in protein levels of the tumor suppressor p27. PPM1H dephosphorylates p27 at threonine 187, thus removing a signal for proteasomal degradation. We further determined that patients whose tumors express low levels of PPM1H trend towards worse clinical outcome on trastuzumab. Identifying PPM1H as a novel p27 phosphatase reveals new insight into how cancer cells destabilize a well-recognized tumor suppressor. Furthermore, low PPM1H expression may identify a subset of HER2-positive tumors that are harder to treat. Significance: PPM1H is identified as a phosphatase impacting p27 stability. Low expression of PPM1H may be associated with poor outcome in breast cancer. Cancer Discovery; 1(4); 326–337. ©2011 AACR. Read the Commentary on this article by Aceto and Bentires-Alj, p. 285 This article is highlighted in the In This Issue feature, p. 275

show abstract

Basal-HER2 phenotype shows poorer survival than basal-like phenotype in hormone receptor-negative invasive breast cancers

Cited by 63 publications

References 20 publications

Pathway-focused proteomic signatures in HER2-overexpressing breast cancer with a basal-like phenotype: New insights into de novo resistance to trastuzumab (Herceptin)

Pathway-focused proteomic signatures in HER2-overexpressing breast cancer with a basal-like phenotype: New insights into de novo resistance to trastuzumab (Herceptin)

Suppression of HER2/HER3-Mediated Growth of Breast Cancer Cells with Combinations of GDC-0941 PI3K Inhibitor, Trastuzumab, and Pertuzumab

PPM1H Is a p27 Phosphatase Implicated in Trastuzumab Resistance

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