scholarly journals Differential Regulation and Targeting of Estrogen Receptor α Turnover in Invasive Lobular Breast Carcinoma

Endocrinology ◽  
2020 ◽  
Vol 161 (9) ◽  
Author(s):  
Sreeja Sreekumar ◽  
Kevin M Levine ◽  
Matthew J Sikora ◽  
Jian Chen ◽  
Nilgun Tasdemir ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Breast Carcinoma ◽  
Cell Lines ◽  
Ductal Carcinoma ◽  
Partial Agonist ◽  
The Cancer Genome Atlas ◽  
Endocrine Treatment ◽  
Term Survival ◽  
Ici 182,780 ◽  
Lobular Breast Carcinoma

Abstract Invasive lobular breast carcinoma (ILC) accounts for 10% to 15% of breast cancers diagnosed annually. Evidence suggests that some aspects of endocrine treatment response might differ between invasive ductal carcinoma (IDC) and ILC, and that patients with ILC have worse long-term survival. We analyzed The Cancer Genome Atlas dataset and observed lower levels of ESR1 mRNA (P = 0.002) and ERα protein (P = 0.038) in ER+ ILC (n = 137) compared to IDC (n = 554), and further confirmed the mRNA difference in a local UPMC cohort (ILC, n = 143; IDC, n = 877; P < 0.005). In both datasets, the correlation between ESR1 mRNA and ERα protein was weaker in ILC, suggesting differential post-transcriptional regulation of ERα. In vitro, 17β-estradiol (E2) decreased the rate of degradation and increased the half-life of ERα in ILC cell lines, whereas the opposite was observed in IDC cell lines. Further, E2 failed to induce robust ubiquitination of ERα in ILC cells. To determine the potential clinical relevance of these findings, we evaluated the effect of 2 selective estrogen receptor downregulators (SERDs), ICI 182,780 and AZD9496, on ERα turnover and cell growth. While ICI 182,780 and AZD9496 showed similar effects in IDC cells, in ILC cell lines, AZD9496 was not as effective as ICI 182,780 in decreasing ERα stability and E2-induced proliferation. Furthermore, AZD9496 exhibited partial agonist activity in growth assays in ILC cell lines. Our study provides evidence for a distinct ERα regulation by SERDs in ILC cell lines, and therefore it is important to include ILC models into preclinical and clinical testing of novel SERDs.

scholarly journals A Rare Metastatic Site of Invasive Lobular Breast Carcinoma: A Case Report

2021 ◽  
Vol 2021 ◽  
pp. 1-5
Author(s):  
Sara Husain ◽  
Mohamed Isa ◽  
Raed Almarzooq
Keyword(s):  
Breast Carcinoma ◽  
Ductal Carcinoma ◽  
Linitis Plastica ◽  
Lobular Breast Cancer ◽  
Gastric Metastasis ◽  
Persistent Vomiting ◽  
Metastatic Site ◽  
Upper Gi ◽  
Upper Gi Endoscopy ◽  
Lobular Breast Carcinoma

Here, we report a case of a 42-year-old female patient with left lobular breast cancer-gastric metastasis (initially misdiagnosed five years ago as an invasive ductal carcinoma) presenting with dyspepsia, weight loss, and persistent vomiting lasting for four weeks. Upper GI endoscopy revealed evidence of linitis plastica, and histological and immunocytochemical analyses of the biopsy confirmed gastric metastasis secondary to invasive lobular breast carcinoma.

Abstract P1-21-03: Unique estrogen receptor alpha turnover, regulation and targeting in invasive lobular breast carcinoma

2020 ◽  
Author(s):  
Jennifer M Atkinson ◽  
Sreeja Sreekumar ◽  
Kevin M Levine ◽  
Matthew J Sikora ◽  
Jian Chen ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Breast Carcinoma ◽  
Estrogen Receptor Alpha ◽  
Receptor Alpha ◽  
Lobular Breast Carcinoma

scholarly journals Regulation of estrogen receptor concentration and activity by an erbB/HER ligand in breast carcinoma cell lines.

Endocrinology ◽  
1996 ◽  
Vol 137 (10) ◽  
pp. 4322-4330 ◽  
Author(s):  
M Saceda ◽  
T W Grunt ◽  
R Colomer ◽  
M E Lippman ◽  
R Lupu ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Breast Carcinoma ◽  
Cell Lines ◽  
Carcinoma Cell ◽  
Carcinoma Cell Lines ◽  
Receptor Concentration ◽  
Breast Carcinoma Cell Lines

A Novel Model of Estrogen Receptor-Positive Breast Cancer Bone Metastasis with Antiestrogen Responsiveness

2021 ◽  
Author(s):  
Kendall L. Langsten ◽  
Lihong Shi ◽  
Adam S. Wilson ◽  
Brian Westwood ◽  
Maria T. Xie ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Bone Metastasis ◽  
Cell Lines ◽  
Triple Negative Breast Cancer ◽  
Estrogen Receptor Alpha ◽  
Triple Negative ◽  
Receptor Alpha ◽  
Ici 182,780 ◽  
Receptor Modulator

AbstractMost women diagnosed with breast cancer (BC) have estrogen receptor alpha positive (ER+) disease. ER+ BC preferentially metastasizes to bone; at which time it is considered incurable. Treatments for bone metastasis have not advanced in decades, in part due to a lack of appropriate ER+ BC bone metastasis models. We developed an immunocompetent ER+ BC murine model with spontaneous bone metastasis and antiestrogen responsiveness. To do this, we transduced triple-negative (TN) bone-tropic murine BC cell lines 4T1.2 and E0771/Bone to express ERα. These cells were then injected into the mammary fat pads of Balb/c (n=21) or C57Bl/6 (n=27), respectively. Once tumors established, mice were treated with either the selective estrogen receptor modulator (SERM) tamoxifen (TAM), the selective estrogen receptor degrader (SERD) ICI 182,780 (ICI, Faslodex, fulvestrant), or vehicle control for 21 days. Tumor volumes and weights significantly decreased in the ER+ groups treated with TAM and ICI compared with ER+ vehicle-treated groups. Staining for immune profiles and total RNA sequencing demonstrated modified immune cell infiltration between TN and ER-derived tumors. Approximately 25% of the mice with ER+ 4T1.2 tumors developed metastases to long bones while none of the mice with TN tumors developed metastases. This immunocompetent ER+ 4T1.2 BC model may allow for further exploration of ER+ BC bone metastasis mechanisms and for the development of new therapeutics for women diagnosed with bone metastasis from ER+ BC.Simple SummaryEstrogen receptor alpha positive (ER+) breast cancer is the most common subtype of breast cancer. When it metastasizes to bone, it becomes incurable. Little advancement has occurred in the treatment of bone metastasis from ER+ breast cancer, partly due to the lack of animal models. To establish an animal model of ER+ BC, we genetically modified two triple-negative breast cancer cell lines to express ERα and injected the cell lines into murine mammary glands. Mice were treated with standard antiestrogen therapies, the selective estrogen receptor modulator tamoxifen or the selective estrogen receptor degrader ICI 182,780. We found that compared to mice with triple-negative breast cancer, mice with ER+ breast cancer developed bone metastases and were responsive to antiestrogen therapy. This model allows for further exploration of bone metastasis mechanisms and for the development of new therapeutics, translating into improved clinical outcomes for women with bone metastasis from ER+ breast cancer.

scholarly journals Mediator of DNA damage checkpoint 1 (MDC1) is a novel estrogen receptor co-regulator in invasive lobular carcinoma of the breast

2020 ◽  
Author(s):  
Evelyn K. Bordeaux ◽  
Joseph L. Sottnik ◽  
Sanjana Mehrotra ◽  
Sarah E. Ferrara ◽  
Andrew E. Goodspeed ◽  
...  
Keyword(s):  
Dna Damage ◽  
Estrogen Receptor ◽  
Tumor Suppressor ◽  
Cell Lines ◽  
Invasive Lobular Carcinoma ◽  
Ductal Carcinoma ◽  
Lobular Carcinoma ◽  
Laboratory Data ◽  
Published Data ◽  
Dna Damage Checkpoint

ABSTRACTInvasive lobular carcinoma (ILC) is the most common histological subtype of breast cancer, and nearly all ILC tumors express estrogen receptor alpha (ER). However, clinical and laboratory data suggest ILC are strongly estrogen-driven but not equally sensitive to anti-estrogen therapies. We hypothesized that ILC-specific ER transcriptional co-regulators mediate ER functions in ILC and anti-estrogen resistance, and profiled ER-associated proteins by mass spectrometry. Three ER+ ILC cell lines, MDA MB 134VI, SUM44PE, and BCK4, were compared to published data from ER+ invasive ductal carcinoma (IDC) cell lines, and we examined whether siRNA knockdown of identified proteins suppressed ER-driven proliferation in ILC cells. This approach found mediator of DNA damage checkpoint 1 (MDC1), a key tumor suppressor in DNA damage response (DDR), as a putative novel ER co-regulator in ILC. We confirmed ER:MDC1 interaction was specific to ILC cell lines versus IDC cells, and found MDC1 knockdown suppressed ILC cell proliferation and suppressed tamoxifen resistance in MDA MB 134VI. Using RNA-sequencing, we found that in ILC cells, MDC1 knockdown broadly dysregulates the estrogen-driven ER transcriptome, with ER:MDC1 target genes enriched for hormone-response-elements in their promoter regions. Importantly, our data are inconsistent with MDC1 regulating ER via MDC1 DDR and tumor suppressor functions, but instead suggest a novel oncogenic role for MDC1 in mediating ER transcriptional activity as a co-regulator. Supporting this, in breast tumor tissue microarrays MDC1 protein was frequently low or absent in IDC or ER-ILC, but MDC1 loss is rare in ER+ ILC. ER:MDC1 interaction and MDC1 co-regulator functions may underlie cell type-specific ER functions in ILC, and serve as important biomarkers and therapeutic targets to overcome anti-estrogen resistance in ILC.

scholarly journals OR12-05 MDC1 Is a Novel Estrogen Receptor Co-Regulator in Invasive Lobular Carcinoma of the Breast

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Evelyn K Bordeaux ◽  
Joseph L Sottnik ◽  
Andrew E Goodspeed ◽  
Sarah E Ferrara ◽  
James C Costello ◽  
...  
Keyword(s):  
Dna Damage ◽  
Estrogen Receptor ◽  
Cell Lines ◽  
Invasive Lobular Carcinoma ◽  
Target Genes ◽  
Ductal Carcinoma ◽  
Lobular Carcinoma ◽  
Er Positive ◽  
Pioneer Factor ◽  
Endogenous Proteins

Abstract Invasive Lobular Carcinoma (ILC) is the 2nd most common histotype of breast cancer, but is critically understudied. ~95% of ILC are estrogen receptor (ER) positive, and previous studies demonstrate the importance of estrogen in ILC etiology. However, retrospective studies show that anti-estrogens are substantially less effective in ILC than in ER+ Invasive Ductal Carcinoma (IDC). This strongly suggests that regulation of ER function is unique in ILC, and we hypothesize that this is due to an ILC-specific cohort of ER co-regulators. We performed Rapid Immunoprecipitation Mass Spectrometry of Endogenous Proteins (RIME) to determine ILC-specific ER-interacting proteins, and identified Mediator of DNA Damage Checkpoint 1 (MDC1) as a novel ER co-regulator in ILC cells. We confirmed ER:MDC1 interaction by co-immunoprecipitation and proximity ligation assays (PLA); interaction was specifically observed in ILC cell lines but not IDC cell lines. Consistent with co-regulator function, we found MDC1 is essential for ER-driven proliferation of ILC cells. MDC1 knockdown dysregulates transcription of ER target genes in ILC cells (e.g. IGFBP4, WNT4). Moreover, RNA-seq analysis showed that in ILC cell line MDA MB 134VI, >50% of ER target genes require MDC1 for their regulation. To understand how MDC1 controls ER transcriptional activity, we performed ChIP-qPCR and found that MDC1 controls ER binding to DNA in ILC cells. Further, MDC1 controls binding of the pioneer factor FOXA1 to DNA, and Dual PLA studies of ER:MDC1 and ER:FOXA1 interaction revealed that MDC1 knockdown decreased ER:FOXA1 interaction. MDC1 canonically functions in DNA damage response, but our preliminary data suggest MDC1 is decoupled from its canonical role in DDR in the context of ER co-regulator activity in ILC cells. Together, these data suggest MDC1, independent of its role in DDR, acts as a novel ER co-regulator in ILC and regulates ER:DNA binding and ER transcriptional function to drive ILC cell proliferation and survival.

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