Amphiregulin deletion strongly attenuates the development of estrogen receptor-positive tumors in p53 mutant mice

Meier, David R.; Girtman, Megan A.; Lofgren, Kristopher A.

doi:10.1007/s10549-019-05507-2

Cited by 6 publications

(3 citation statements)

References 24 publications

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“…Expression of total AREG in several of these tumors had previously been described [ 5–9 ], but evidence for a functional requirement for AREG has been limited to a smaller group, including colorectal [ 10 ] and breast cancer [ 6 , 11 ]. In parallel, our studies in normal tissues highlight the prevalence of AREG cleavage during normal tissue homeostasis.…”

Section: Discussionmentioning

confidence: 99%

Pan-cancer distribution of cleaved cell-surface amphiregulin, the target of the GMF-1A3 antibody drug conjugate

Lofgren

Reker

Sreekumar

2022

Antibody Therapeutics

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Amphiregulin is a transmembrane protein which, when cleaved by the TACE/ADAM17 protease, releases a soluble Epidermal Growth Factor Receptor ligand domain that promotes proliferation of normal and malignant cells. We previously described a rabbit monoclonal antibody, GMF-1A3, that selectively recognizes the cell-associated cleaved Amphiregulin epitope. Antibody-drug conjugates had anti-tumor activity against human breast cancer xenografts. Several tumor types express Amphiregulin, but evidence for a functional requirement for Amphiregulin in these malignancies is limited. By directly evaluating Amphiregulin cleavage with immunohistochemistry, GMF-1A3 provides a more direct measure of Amphiregulin activity. Using 370 specimens from 10 tumor types (as well as normal controls), we demonstrate that cleaved Amphiregulin is widely expressed in solid tumors and is especially common (> 50% of cases) in breast, prostate, liver and lung cancer. As a potential companion diagnostic for this antibody-drug conjugate, this assay allows identification of tumors with high levels of the cleaved Amphiregulin target.

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Section: Discussionmentioning

confidence: 99%

Pan-cancer distribution of cleaved cell-surface amphiregulin, the target of the GMF-1A3 antibody drug conjugate

Lofgren

Reker

Sreekumar

2022

Antibody Therapeutics

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“…Expression of total Amphiregulin in several of these tissues had previously been described [5][6][7][8][9], but evidence for a functional requirement for Amphiregulin has been limited to a smaller group, including colorectal [10] and breast cancer [6,11]. Our demonstration here that the expressed Amphiregulin is being actively cleaved in a wide range of cancer types confirms that autocrine Amphiregulin signaling following ADAM17-dependent Amphiregulin cleavage is commonly occurring, raising the possibility that Amphiregulin-dependent EGFR activation may be a more frequent mitogenic signal that has been previously appreciated.…”

Section: Discussionmentioning

confidence: 99%

Pan-cancer distribution of cleaved cell-surface Amphiregulin, the target of the GMF-1A3 antibody drug conjugate

Lofgren

Reker

Sreekumar

2022

Preprint

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Amphiregulin (AREG) is a transmembrane protein which, following TACE/ADAM17-dependent cleavage, releases a soluble Epidermal Growth Factor Receptor ligand domain that promotes proliferation of normal and malignant cells. Expression of Amphiregulin has been described by immunohistochemistry in several tumor types, including lung, prostate, head and neck, gastric, pancreatic and breast cancers but evidence for a functional requirement for Amphiregulin in these malignancies is more limited. We have previously described the development of a monoclonal antibody, GMF-1A3, that selectively recognizes the Amphiregulin epitope that is revealed following cleavage by TACE/ADAM17 and demonstrated that drug conjugates of this antibody have anti-tumor activity in mouse models. By directly evaluating Amphiregulin cleavage, immunohistochemistry on tissue specimens using this antibody can be used to evaluate the extent to which Amphiregulin is being proteolytically processed in cancer, which is a more direct measure of Amphiregulin activity. As a potential companion diagnostic for this antibody-drug conjugate, this immunohistochemistry assay allows identification of tumors with high levels of the cleaved Amphiregulin target. Here we evaluate levels of cleaved Amphiregulin in 370 specimens from 10 tumor types and demonstrate that it is widely expressed in solid tumors and is especially common (more than 50% of cases) in breast, prostate, liver and lung cancer.

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“…AREG is a critical paracrine or autocrine regulator of estrogen action in mammary gland development required for ductal morphogenesis (Ciarloni et al 2007). Recent studies have reported that AREG is enriched in ER+ breast tumor cells and required for estrogen-dependent tumor growth (Peterson et al 2015, Meier et al 2020. Emerging evidence suggests that deregulation of AREG is also associated with drug resistance and metastasis in many cancers (Xu et al 2016).…”

Section: Introductionmentioning

confidence: 99%

Amphiregulin retains ERα expression in acquired aromatase inhibitor resistant breast cancer cells

Wang

Tzeng

Chang

et al. 2020

Endocrine-Related Cancer

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Acquired resistance to aromatase inhibitors (AIs) is a significant clinical issue in endocrine therapy for estrogen receptor (ER) positive breast cancer which accounts for the majority of breast cancer. Despite estrogen production being suppressed, ERα signaling remains active and plays a key role in most AI-resistant breast tumors. Here, we found that amphiregulin (AREG), an ERα transcriptional target and epidermal growth factor receptor (EGFR) ligand, is crucial for maintaining ERα expression and signaling in acquired AI-resistant breast cancer cells. AREG was deregulated and critical for cell viability in ER+ AI-resistant breast cancer cells, and ectopic expression of AREG in hormone responsive breast cancer cells promoted endocrine resistance. RNA-sequencing and reverse phase protein array analyses revealed that AREG maintains ERα expression and signaling by activation of PI3K/Akt/mTOR signaling and upregulation of forkhead box M1 (FoxM1) and serum- and glucocorticoid-inducible kinase 3 (SGK3) expression. Our study uncovers a previously unappreciated role of AREG in maintaining ERα expression and signaling, and establishes the AREG-ERα crosstalk as a driver of acquired AI resistance in breast cancer.

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Amphiregulin deletion strongly attenuates the development of estrogen receptor-positive tumors in p53 mutant mice

Cited by 6 publications

References 24 publications

Pan-cancer distribution of cleaved cell-surface amphiregulin, the target of the GMF-1A3 antibody drug conjugate

Pan-cancer distribution of cleaved cell-surface amphiregulin, the target of the GMF-1A3 antibody drug conjugate

Pan-cancer distribution of cleaved cell-surface Amphiregulin, the target of the GMF-1A3 antibody drug conjugate

Amphiregulin retains ERα expression in acquired aromatase inhibitor resistant breast cancer cells

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