Estrogen promotes estrogen receptor negative BRCA1-deficient tumor initiation and progression

Wang, Chuying; Bai, Feng; Zhang, Li han; Scott, Alexandria; Li, Enxiao; Pei, Xin-Hai

doi:10.1186/s13058-018-0996-9

Cited by 28 publications

(25 citation statements)

References 56 publications

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“…Furthermore, Pdgfrβ mRNA levels in p18 −/− ; Brca1 +/− mammary tumors strongly correlated with EMT and stem cell signatures (Fig. 1 e, f, and Additional file 2 B, C, D), in agreement with the data derived from IHC and published elsewhere [ 31 , 59 ]. Together, these results suggest that germline deletion of Brca1 in a p18 −/− background activates EMT in mammary tumorigenesis, which is associated with an increase of Pdgfrβ and Pdgfrβ-activated signaling pathway.…”

Section: Resultssupporting

confidence: 90%

“…We previously discovered that the majority of p18 −/− mice developed CK8 + and ER + luminal type mammary tumors while most p18 −/− ; Brca1 +/− mice formed mammary tumors that were ER − and CK5 + basal-like tumors expressing mesenchymal markers as well as EMT-TFs [ 11 , 28 , 31 ]. In addition, p18 −/− ; Brca1 +/− mammary tumors were enriched with cancer stem cells [ 31 , 59 ] and significantly more metastatic than p18 −/− tumors (Fig. 1 a).…”

Section: Resultsmentioning

confidence: 99%

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PDGFRβ is an essential therapeutic target for BRCA1-deficient mammary tumors

et al. 2021

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Background Basal-like breast cancers (BLBCs) are a leading cause of cancer death due to their capacity to metastasize and lack of effective therapies. More than half of BLBCs have a dysfunctional BRCA1. Although most BRCA1-deficient cancers respond to DNA-damaging agents, resistance and tumor recurrence remain a challenge to survival outcomes for BLBC patients. Additional therapies targeting the pathways aberrantly activated by BRCA1 deficiency are urgently needed. Methods Most BRCA1-deficient BLBCs carry a dysfunctional INK4-RB pathway. Thus, we created genetically engineered mice with Brca1 loss and deletion of p16INK4A, or separately p18INK4C, to model the deficient INK4-RB signaling in human BLBC. By using these mutant mice and human BRCA1-deficient and proficient breast cancer tissues and cells, we tested if there exists a druggable target in BRCA1-deficient breast cancers. Results Heterozygous germline or epithelium-specific deletion of Brca1 in p18INK4C- or p16INK4A-deficient mice activated Pdgfrβ signaling, induced epithelial-to-mesenchymal transition, and led to BLBCs. Confirming this role, targeted deletion of Pdgfrβ in Brca1-deficient tumor cells promoted cell death, induced mesenchymal-to-epithelial transition, and suppressed tumorigenesis. Importantly, we also found that pharmaceutical inhibition of Pdgfrβ and its downstream target Pkcα suppressed Brca1-deficient tumor initiation and progression and effectively killed BRCA1-deficient cancer cells. Conclusions Our work offers the first genetic and biochemical evidence that PDGFRβ-PKCα signaling is repressed by BRCA1, which establishes PDGFRβ-PKCα signaling as a therapeutic target for BRCA1-deficient breast cancers.

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Section: Resultssupporting

confidence: 90%

Section: Resultsmentioning

confidence: 99%

PDGFRβ is an essential therapeutic target for BRCA1-deficient mammary tumors

et al. 2021

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“…A high number of loss-of-heterozygosity events at the BRCA1 genomic locus in ER-positive tumors from BRCA1 mutation carriers found in this study (83%) and in a study by Tung and colleagues (81%) indicates that BRCA1 impairment directly contributes to the formation of ER-positive tumors [28]. The mechanism explaining how ER signaling can contribute to worsened BC progression in BRCA1/BRCA2 mutation carriers is unknown; however, preclinical data demonstrated estrogen-dependent progression of mammary tumorigenesis in BRCA1-defficient cells [29,30]. Shah and colleagues have analyzed OncotypeDX in BRCA1/BRCA2 mutation carriers with ER-positive tumors and found a high proportion of patients with a high recurrence score who may benefit from adjuvant chemotherapy [31].…”

Section: Discussionmentioning

confidence: 62%

Estrogen Receptor Status Oppositely Modifies Breast Cancer Prognosis in BRCA1/BRCA2 Mutation Carriers Versus Non-Carriers

Vočka

Zimovjanová

Bielčiková

et al. 2019

Cancers

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Breast cancer (BC) prognosis in BRCA1 and BRCA2 mutation carriers has been reported contradictorily, and the significance of variables influencing prognosis in sporadic BC is not established in BC patients with hereditary BRCA1/BRCA2 mutations. In this retrospective cohort study, we analyzed the effect of clinicopathological characteristics on BC prognosis (disease-free survival [DFS] and disease-specific survival [DSS]) in hereditary BRCA1/BRCA2 mutation carriers. We enrolled 234 BRCA1/BRCA2 mutation carriers and 899 non-carriers, of whom 191 carriers and 680 non-carriers, with complete data, were available for survival analyses. We found that patients with ER-positive tumors developed disease recurrence 2.3-times more likely when they carried a BRCA1/BRCA2 mutation (23/60; 38.3% ER-positive carriers vs. 74/445; 16.6% ER-positive non-carriers; p < 0.001). ER-positive mutation carriers also had a 3.4-times higher risk of death due to BC compared with ER-positive non-carriers (13/60; 21.7% vs. 28/445; 6.3%; p < 0.001). Moreover, prognosis in ER-negative BRCA1/BRCA2 mutation carriers was comparable with that in ER-positive non-carriers. Our study demonstrates that ER-positivity worsens BC prognosis in BRCA1/BRCA2 mutation carriers, while prognosis for carriers with ER-negative tumors (including early-onset) is significantly better and comparable with that in ER-positive, older BC non-carriers. These observations indicate that BRCA1/BRCA2 mutation carriers with ER-positive BC represent high-risk patients.

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“…Normally, BRCA1 negatively regulates the PI3K/AKT pathway through ubiquitination of p-AKT, leading to its degradation [51]. Activation of this pathway in BRCA1-deficient breast cancer leads to EMT, cell motility, and tumor progression and metastasis [52, 53]. We found that fisetin downregulated signaling molecules of PI3K/AKT pathway including AKT(S473/T308), P70S6K(T421/S424 and T389), and PRAS40 by 54–75%.…”

Section: Discussionmentioning

confidence: 99%

Phytochemicals inhibit migration of triple negative breast cancer cells by targeting kinase signaling

et al. 2020

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BackgroundCell migration and invasion are essential processes for metastatic dissemination of cancer cells. Significant progress has been made in developing new therapies against oncogenic signaling to eliminate cancer cells and shrink tumors. However, inherent heterogeneity and treatment-induced adaptation to drugs commonly enable subsets of cancer cells to survive therapy. In addition to local recurrence, these cells escape a primary tumor and migrate through the stroma to access the circulation and metastasize to different organs, leading to an incurable disease. As such, therapeutics that block migration and invasion of cancer cells may inhibit or reduce metastasis and significantly improve cancer therapy. This is particularly more important for cancers, such as triple negative breast cancer, that currently lack targeted drugs.MethodsWe used cell migration, 3D invasion, zebrafish metastasis model, and phosphorylation analysis of 43 protein kinases in nine triple negative breast cancer (TNBC) cell lines to study effects of fisetin and quercetin on inhibition of TNBC cell migration, invasion, and metastasis.ResultsFisetin and quercetin were highly effective against migration of all nine TNBC cell lines with up to 76 and 74% inhibitory effects, respectively. In addition, treatments significantly reduced 3D invasion of highly motile TNBC cells from spheroids into a collagen matrix and their metastasis in vivo. Fisetin and quercetin commonly targeted different components and substrates of the oncogenic PI3K/AKT pathway and significantly reduced their activities. Additionally, both compounds disrupted activities of several protein kinases in MAPK and STAT pathways. We used molecular inhibitors specific to these signaling proteins to establish the migration-inhibitory role of the two phytochemicals against TNBC cells.ConclusionsWe established that fisetin and quercetin potently inhibit migration of metastatic TNBC cells by interfering with activities of oncogenic protein kinases in multiple pathways.

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Estrogen promotes estrogen receptor negative BRCA1-deficient tumor initiation and progression

Cited by 28 publications

References 56 publications

PDGFRβ is an essential therapeutic target for BRCA1-deficient mammary tumors

PDGFRβ is an essential therapeutic target for BRCA1-deficient mammary tumors

Estrogen Receptor Status Oppositely Modifies Breast Cancer Prognosis in BRCA1/BRCA2 Mutation Carriers Versus Non-Carriers

Phytochemicals inhibit migration of triple negative breast cancer cells by targeting kinase signaling

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