Issues Affecting the Loco-regional and Systemic Management of Patients with Invasive Lobular Carcinoma of the Breast

Jacobs, Carmel; Clemons, Mark; Addison, Christina L.; Robertson, Susan J.; Arnaout, Angel

doi:10.1111/tbj.12520

Cited by 16 publications

(9 citation statements)

References 87 publications

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“…ILCs typically present with clinical biomarkers consistent with endocrine responsiveness, and nearly all patients with ILC are treated with adjuvant endocrine therapy [ 1 , 36 ]. However, recent retrospective clinical trial data suggest that at least a subset of patients with ILC may have poor outcomes with endocrine therapy [ 6 , 7 ], suggesting that, compared with IDC, ER biology and signaling may be unique in ILC cells.…”

Section: Discussionmentioning

confidence: 99%

WNT4 mediates estrogen receptor signaling and endocrine resistance in invasive lobular carcinoma cell lines

et al. 2016

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BackgroundInvasive lobular carcinoma (ILC) of the breast typically presents with clinical biomarkers consistent with a favorable response to endocrine therapies, and over 90 % of ILC cases express the estrogen receptor (ER). However, a subset of ILC cases may be resistant to endocrine therapies, suggesting that ER biology is unique in ILC. Using ILC cell lines, we previously demonstrated that ER regulates a distinct gene expression program in ILC cells, and we hypothesized that these ER-driven pathways modulate the endocrine response in ILC. One potential novel pathway is via the Wnt ligand WNT4, a critical signaling molecule in mammary gland development regulated by the progesterone receptor.MethodsThe ILC cell lines MDA-MB-134-VI, SUM44PE, and BCK4 were used to assess WNT4 gene expression and regulation, as well as the role of WNT4 in estrogen-regulated proliferation. To assess these mechanisms in the context of endocrine resistance, we developed novel ILC endocrine-resistant long-term estrogen-deprived (ILC-LTED) models. ILC and ILC-LTED cell lines were used to identify upstream regulators and downstream signaling effectors of WNT4 signaling.ResultsILC cells co-opted WNT4 signaling by placing it under direct ER control. We observed that ER regulation of WNT4 correlated with use of an ER binding site at the WNT4 locus, specifically in ILC cells. Further, WNT4 was required for endocrine response in ILC cells, as WNT4 knockdown blocked estrogen-induced proliferation. ILC-LTED cells remained dependent on WNT4 for proliferation, by either maintaining ER function and WNT4 regulation or uncoupling WNT4 from ER and upregulating WNT4 expression. In the latter case, WNT4 expression was driven by activated nuclear factor kappa-B signaling in ILC-LTED cells. In ILC and ILC-LTED cells, WNT4 led to suppression of CDKN1A/p21, which is critical for ILC cell proliferation. CDKN1A knockdown partially reversed the effects of WNT4 knockdown.ConclusionsWNT4 drives a novel signaling pathway in ILC cells, with a critical role in estrogen-induced growth that may also mediate endocrine resistance. WNT4 signaling may represent a novel target to modulate endocrine response specifically for patients with ILC.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-016-0748-7) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

WNT4 mediates estrogen receptor signaling and endocrine resistance in invasive lobular carcinoma cell lines

et al. 2016

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“…Figure 3 illustrates the utility of 18 F-FES PET in a patient with invasive lobular carcinoma (ILC) of the breast. ILC is characterized by a disseminated growth pattern, low proliferation, and lower tumor glycolysis than invasive ductal carcinomas, while carrying a poor prognosis considering its relative indolence [47,48]. In addition to creating unique challenges for diagnosis and treatment, ILC features such as dissemination and indolence cast doubt on the utility of 18 F-FDG PET for staging [48].…”

Section: Clinical Applications For 18 F-fes Petmentioning

confidence: 99%

Whole-Body Characterization of Estrogen Receptor Status in Metastatic Breast Cancer with 16α-18F-Fluoro-17β-Estradiol Positron Emission Tomography: Meta-Analysis and Recommendations for Integration into Clinical Applications

Kurland

Wiggins²,

Coche³

et al. 2020

The Oncologist

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Estrogen receptor (ER) status by immunohistochemistry (IHC) of cancer tissue is currently used to direct endocrine therapy in breast cancer. Positron emission tomography (PET) with 16α-18F-fluoro-17β-estradiol (18 F-FES) noninvasively characterizes ER ligand-binding function of breast cancer lesions. Concordance of imaging and tissue assays should be established for 18 F-FES PET to be an alternative or complement to tissue biopsy for metastatic lesions. We conducted a metaanalysis of published results comparing 18 F-FES PET and tissue assays of ER status in patients with breast cancer. PubMed and EMBASE were searched for English-language manuscripts with at least 10 patients and low overall risk of bias. Thresholds for imaging and tissue classification could differ between studies but had to be clearly stated. We used hierarchical summary receiver-operating characteristic curve models for the meta-analysis. The primary analysis included 113 nonbreast lesions from 4 studies; an expanded analysis included 327 total lesions from 11 studies. Treating IHC results as the reference standard, sensitivity was 0.78 (95% confidence region 0.65-0.88) and specificity 0.98 (0.65-1.00) for the primary analysis of nonbreast lesions. In the expanded analysis including non-IHC tissue assays and all lesion sites, sensitivity was 0.81 (0.73-0.87) and specificity 0.86 (0.68-0.94). These results suggest that 18 F-FES PET is useful for characterization of ER status of metastatic breast cancer lesions. We also review current best practices for conducting 18 F-FES PET scans. This imaging assay has potential to improve clinically relevant outcomes for patients with (historically) ER-positive metastatic breast cancer, including those with brain metastases and/or lobular histology.

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“…1 After invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC) of the breast is the second most common type of invasive breast carcinoma, accounting for 8% to 14% of all breast cancers. [2][3][4][5][6][7] ILC is pathologically, clinically, and biologically unique among breast cancers. 2 Traditionally, ILC presents as a number of histologic subtypes based on morphology.…”

Section: Introductionmentioning

confidence: 99%

“…[2][3][4][5][6][7] ILC is pathologically, clinically, and biologically unique among breast cancers. 2 Traditionally, ILC presents as a number of histologic subtypes based on morphology. 8 Pleomorphic lobular breast carcinoma (PLC) is a uncommon but clinically important form of ILC.…”

Section: Introductionmentioning

confidence: 99%

Invasive Pleomorphic Lobular Carcinoma of the Breast: Pathologic, Clinical, and Therapeutic Considerations

Al-Baimani

Bazzarelli

Clemons

et al. 2015

Clinical Breast Cancer

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Issues Affecting the Loco-regional and Systemic Management of Patients with Invasive Lobular Carcinoma of the Breast

Cited by 16 publications

References 87 publications

WNT4 mediates estrogen receptor signaling and endocrine resistance in invasive lobular carcinoma cell lines

WNT4 mediates estrogen receptor signaling and endocrine resistance in invasive lobular carcinoma cell lines

Whole-Body Characterization of Estrogen Receptor Status in Metastatic Breast Cancer with 16α-18F-Fluoro-17β-Estradiol Positron Emission Tomography: Meta-Analysis and Recommendations for Integration into Clinical Applications

Invasive Pleomorphic Lobular Carcinoma of the Breast: Pathologic, Clinical, and Therapeutic Considerations

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