scholarly journals Stromal NRG1 in luminal breast cancer defines pro-fibrotic and migratory cancer-associated fibroblasts

Oncogene ◽  
2021 ◽  
Author(s):  
Mireia Berdiel-Acer ◽  
Ana Maia ◽  
Zhivka Hristova ◽  
Simone Borgoni ◽  
Martina Vetter ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumour Progression ◽  
Phase 1 ◽  
Single Agent ◽  
Therapy Resistance ◽  
Luminal Breast Cancer ◽  
Cancer Associated Fibroblasts ◽  
Cancer Subtypes ◽  
Elevated Expression ◽  
Hyaluronan Synthase 2

AbstractHER3 is highly expressed in luminal breast cancer subtypes. Its activation by NRG1 promotes activation of AKT and ERK1/2, contributing to tumour progression and therapy resistance. HER3-targeting agents that block this activation, are currently under phase 1/2 clinical studies, and although they have shown favorable tolerability, their activity as a single agent has proven to be limited. Here we show that phosphorylation and activation of HER3 in luminal breast cancer cells occurs in a paracrine manner and is mediated by NRG1 expressed by cancer-associated fibroblasts (CAFs). Moreover, we uncover a HER3-independent NRG1 signaling in CAFs that results in the induction of a strong migratory and pro-fibrotic phenotype, describing a subtype of CAFs with elevated expression of NRG1 and an associated transcriptomic profile that determines their functional properties. Finally, we identified Hyaluronan Synthase 2 (HAS2), a targetable molecule strongly correlated with NRG1, as an attractive player supporting NRG1 signaling in CAFs.

scholarly journals Stromal NRG1 in luminal breast cancer defines pro-fibrotic and migratory cancer-associated fibroblasts

2020 ◽  
Author(s):  
Mireia Berdiel-Acer ◽  
Ana Maia ◽  
Zhivka Hristova ◽  
Simone Borgoni ◽  
Martina Vetter ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumour Progression ◽  
Phase 1 ◽  
Single Agent ◽  
Therapy Resistance ◽  
Luminal Breast Cancer ◽  
Cancer Associated Fibroblasts ◽  
Autocrine Signaling ◽  
Cancer Subtypes ◽  
Elevated Expression

AbstractHER3 is highly expressed in luminal breast cancer subtypes. Its activation by NRG1 promotes activation of AKT and ERK1/2, contributing to tumour progression and therapy resistance. HER3-targeting agents that block this activation, are currently under phase 1/2 clinical studies, and although they have shown favorable tolerability, their activity as a single agent has proven to be limited. Here we show that phosphorylation and activation of HER3 in luminal breast cancer cells occurs in a paracrine manner and is mediated by NRG1 expressed by cancer-associated fibroblasts (CAFs). Moreover, we uncover an autocrine role of NRG1 in CAFs. This occurs independently of HER3 and results in the induction of a strong migratory and pro-fibrotic phenotype, describing a subset of CAFs with elevated expression of NRG1 and an associated transcriptomic profile that determines their functional properties. Finally, we identified Hyaluronan Synthase 2 (HAS2), a targetable molecule strongly correlated with NRG1, as an attractive player supporting NRG1 - autocrine signaling in CAFs.

scholarly journals Genomic Signatures in Luminal Breast Cancer

Breast Care ◽  
2020 ◽  
Vol 15 (4) ◽  
pp. 355-365
Author(s):  
Julian Puppe ◽  
Tabea Seifert ◽  
Christian Eichler ◽  
Henryk Pilch ◽  
Peter Mallmann ◽  
...  
Keyword(s):  
Breast Cancer ◽  
High Throughput Sequencing ◽  
Early Stage ◽  
Intrinsic Subtype ◽  
Luminal Breast Cancer ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Cancer Subtypes ◽  
Molecular Tests ◽  
Immunohistochemical Markers

Background: Breast cancer is a very heterogeneous disease and luminal breast carcinomas represent the hormone receptor-positive tumors among all breast cancer subtypes. In this context, multigene signatures were developed to gain further prognostic and predictive information beyond clinical parameters and traditional immunohistochemical markers. Summary: For early breast cancer patients these molecular tools can guide clinicians to decide on the extension of endocrine therapy to avoid over- and undertreatment by adjuvant chemotherapy. Beside the predictive and prognostic value, a few genomic tests are also able to provide intrinsic subtype classification. In this review, we compare the most frequently used and commercially available molecular tests (OncotypeDX®, MammaPrint®, Prosigna®, EndoPredict®, and Breast Cancer IndexSM). Moreover, we discuss the clinical utility of molecular profiling for advanced breast cancer of the luminal subtype. Key Messages: Multigene assays can help to de-escalate systemic therapy in early-stage breast cancer. Only the Oncotype DX® and MammaPrint®test are validated by entirely prospective and randomized phase 3 trials. More clinical evidence is needed to support the use of genomic tests in node-positive disease. Recent developments in high-throughput sequencing technology will provide further insights to understand the heterogeneity of luminal breast cancers in early-stage and metastatic disease.

scholarly journals Mechanisms of CDK4/6 Inhibitor Resistance in Luminal Breast Cancer

2020 ◽  
Vol 11 ◽  
Author(s):  
Zhen Li ◽  
Wei Zou ◽  
Ji Zhang ◽  
Yunjiao Zhang ◽  
Qi Xu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Therapy Resistance ◽  
Resistance Mechanisms ◽  
Cancer Drug ◽  
Luminal Breast Cancer ◽  
Cancer Drug Resistance ◽  
Estrogen Receptor Positive ◽  
Underlying Mechanisms ◽  
Inhibitor Resistance ◽  
New Generation

As a new-generation CDK inhibitor, a CDK4/6 inhibitor combined with endocrine therapy has been successful in the treatment of advanced estrogen receptor–positive (ER+) breast cancer. Although there has been overall progress in the treatment of cancer, drug resistance is an emerging cause for breast cancer–related death. Overcoming CDK4/6 resistance is an urgent problem. Overactivation of the cyclin-CDK-Rb axis related to uncontrolled cell proliferation is the main cause of CDK4/6 inhibitor resistance; however, the underlying mechanisms need to be clarified further. We review various resistance mechanisms of CDK4/6 inhibitors in luminal breast cancer. The cell signaling pathways involved in therapy resistance are divided into two groups: upstream response mechanisms and downstream bypass mechanisms. Finally, we discuss possible strategies to overcome CDK4/6 inhibitor resistance and identify novel resistance targets for future clinical application.

Final results of a phase 1 study of single-agent veliparib (V) in patients (pts) with either BRCA1/2-mutated cancer (BRCA+), platinum-refractory ovarian, or basal-like breast cancer (BRCA-wt).

2014 ◽  
Vol 32 (15_suppl) ◽  
pp. 2570-2570 ◽  
Author(s):  
Shannon Puhalla ◽  
Jan Hendrik Beumer ◽  
Shalu Pahuja ◽  
Leonard Joseph Appleman ◽  
Hussein Abdul-Hassan Tawbi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phase 1 ◽  
Single Agent ◽  
Phase 1 Study ◽  
Basal Like Breast Cancer ◽  
Platinum Refractory

scholarly journals Overcoming Therapy Resistance and Relapse in TNBC: Emerging Technologies to Target Breast Cancer-Associated Fibroblasts

Biomedicines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1921
Author(s):  
Farhana Mollah ◽  
Pegah Varamini
Keyword(s):  
Breast Cancer ◽  
Small Molecules ◽  
Cancer Progression ◽  
Triple Negative ◽  
Chemotherapy Resistance ◽  
Therapy Resistance ◽  
Cancer Associated Fibroblasts ◽  
Aggressive Form ◽  
Promising Target ◽  
Wide Range

Breast cancer is the most diagnosed cancer and is the leading cause of cancer mortality in women. Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer. Often, TNBC is not effectively treated due to the lack of specificity of conventional therapies and results in relapse and metastasis. Breast cancer-associated fibroblasts (BCAFs) are the predominant cells that reside in the tumor microenvironment (TME) and regulate tumorigenesis, progression and metastasis, and therapy resistance. BCAFs secrete a wide range of factors, including growth factors, chemokines, and cytokines, some of which have been proved to lead to a poor prognosis and clinical outcomes. This TME component has been emerging as a promising target due to its crucial role in cancer progression and chemotherapy resistance. A number of therapeutic candidates are designed to effectively target BCAFs with a focus on their tumor-promoting properties and tumor immune response. This review explores various agents targeting BCAFs in TNBC, including small molecules, nucleic acid-based agents, antibodies, proteins, and finally, nanoparticles.

scholarly journals Single cell transcriptomics reveals involution mimicry during the specification of the basal breast cancer subtype

2019 ◽  
Author(s):  
Fatima Valdes-Mora ◽  
Robert Salomon ◽  
Brian Gloss ◽  
Andrew MK. Law ◽  
Lesley Castillo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Single Cell ◽  
Cancer Cells ◽  
Tumour Progression ◽  
Breast Cancer Subtype ◽  
Luminal Breast Cancer ◽  
Luminal Progenitor ◽  
Mesenchymal Transition ◽  
Basal Breast Cancer ◽  
Cancer Subtype

AbstractBoth luminal and basal breast cancer subtypes originate in the mammary luminal progenitor cell compartment. Basal breast cancer is associated with younger age, early relapse, and high mortality rate. Here we used unbiased droplet-based single-cell RNAseq to elucidate the cellular basis of tumour progression during the specification of the basal breast cancer subtype from the luminal progenitor population. Basal–like cancer cells resembled the alveolar lineage that is specified upon pregnancy and showed molecular features indicative of an interaction with the tumour microenvironment (TME) including epithelial-to-mesenchymal transition (EMT), hypoxia, lactation and involution. Involution signatures in luminal breast cancer tumours with alveolar lineage features were associated with worse prognosis and features of basal breast cancer. Our high-resolution molecular characterisation of the tumour ecosystem also revealed a highly interactive cell-cell network reminiscent of an involution process. This involution mimicry involves malignant education of cancer-associated fibroblasts and myeloid cell recruitment to support tissue remodelling and sustained inflammation. Our study shows how luminal breast cancer acquires an aberrant post-lactation developmental program that involves both cancer cells and cells from the TME, to shift molecular subtype and promote tumour progression, with potential to explain the increased risk and poor prognosis of breast cancer associated to childbirth.

scholarly journals Tumorigenic and Metastatic Role of CD44−/low/CD24−/low Cells in Luminal Breast Cancer

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1239 ◽  
Author(s):  
Rajeev Vikram ◽  
Wen Cheng Chou ◽  
Shih-Chieh Hung ◽  
Chen-Yang Shen
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Breast Cancer Subtypes ◽  
Diagnostic Tools ◽  
Breast Cancer Cell Lines ◽  
Luminal Breast Cancer ◽  
Cancer Subtypes ◽  
Tumorigenic Potential ◽  
Mcf 7

Cells with high CD44 but low CD24 expression (CD44high/CD24−/low) and high aldehyde dehydrogenase activity (ALDHbr) are widely considered to be drivers of metastasis, therapy resistance and tumor recurrence in breast cancer. However, the role of the CD44high/CD24−/low and ALDHbr phenotypes in identifying tumorigenic cells in breast cancer remains controversial due to the discrepancy in their distribution and tumorigenic potential in intrinsic breast cancer subtypes. In this study, we analyzed the cells expressing these markers in six different breast cancer cell lines representing major breast cancer subtypes (T47D, MCF-7, BT-474, AU-565, Hs578T and MDA-MB-231). CD44high/CD24−/low, ALDHbr and CD44−/low/CD24−/low cell populations were isolated by flow cytometry and analyzed for hallmark stem cell characteristics of differentiation, migration, invasiveness and metastasis using in vitro and in vivo techniques. Our results demonstrate that the CD44−/low/CD24−/low cell population, which is enriched in luminal cell lines (T47D, MCF-7 and BT-474), possesses metastatic and tumorigenic properties. We also show that, contrary to previous claims, the expression of the ALDH1 isoform ALDH1A1 does not affect the tumorigenic potential of cell lines with high ALDH activity (BT-474 and AU-565). Further transcriptomic and clinical studies are needed to determine the potential of these markers as early diagnostic tools and treatment targets.

A first-in-human phase I study of the CDK4/6 inhibitor, LY2835219, for patients with advanced cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2500-2500 ◽  
Author(s):  
Geoffrey Shapiro ◽  
Lee S. Rosen ◽  
Anthony W. Tolcher ◽  
Jonathan Wade Goldman ◽  
Leena Gandhi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Antitumor Activity ◽  
Advanced Cancer ◽  
Human Cancer ◽  
Phase 1 ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Ca 125 ◽  
Clinical Activity

2500 Background: Cyclin dependent kinases 4 and 6 (CDK4/6) act with D-type cyclins to inactivate the retinoblastoma (Rb) tumor suppressor protein and enable cell cycle progression from G1 to S phase. LY2835219 is a selective inhibitor of CDK4/6 that shows antitumor activity in preclinical models of human cancer and also distributes efficiently to the brain. We performed a phase 1 study to evaluate safety, pharmacokinetics, pharmacodynamics, and antitumor activity of LY2835219. Methods: 3+3 dose escalation was followed by expansions in 5 tumor types (brain metastases permitted): non-small cell lung cancer (NSCLC), glioblastoma, breast cancer, melanoma, and colorectal cancer. LY2835219 was taken orally every 12 or 24 hours (in escalation) and every 12 hours (in expansions) on days 1-28 of a 28-day cycle. Results: 55 patients (pts) received LY2835219. In escalation, 33 pts received LY2835219 on 1 of 2 schedules: 50, 100, 150, 225 mg every 24 hours (Q24H) or 75, 100, 150, 200, 275 mg every 12 hours (Q12H). On the Q24H schedule, the maximum tolerated dose (MTD) was not identified. On the Q12H schedule, the MTD was 200mg Q12H with dose limiting toxicity of G3 fatigue at 200 mg (1/6 evaluable pts) and 275 mg (2/3 evaluable pts). At 200mg Q12H, the mean Cmax and AUC0-24hr at steady state were 285 ng/mL and 5502 ng-hr/ml, respectively. In skin, LY2835219 induced pharmacodynamic inhibition of both Rb phosphorylation and topoisomerase IIα expression. In the ongoing expansions, 22 pts have received LY2835219. Across the study, the most common related adverse events were diarrhea (52%, including 5% G3), nausea (30%, 4% G3), fatigue (21%, 7% G3), vomiting (18%, 2% G3), and neutropenia (16%, 7% G3). 15 pts have reached ≥4 cycles for stable disease or better with 3 pts achieving 8, 16, and 26 cycles. One pt with ovarian cancer had a durable CA-125 response with >50% decrease for 16 cycles. One pt with KRAS mutant NSCLC had a 27% decrease by RECIST. One pt with CDKN2A-/- NRAS mutant melanoma had a confirmed partial response. Early clinical activity has been observed in ovarian cancer, NSCLC, breast cancer, and melanoma. Conclusions: LY2835219 shows acceptable safety and early clinical activity as a single agent for patients with advanced cancer. Clinical trial information: NCT01394016.

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