Involvement of Breast Cancer-Associated Fibroblasts in Tumor Development, Therapy Resistance and Evaluation of Potential Therapeutic Strategies

Breast cancer is the most common cancer in women, which incidence has increased in recent years. It is constituted by very heterogeneous tissue characterized by an abnormal microenvironment regulating tumor progression and providing evasion from cancer therapies. Breast cancer-associated fibroblasts (BCAFs) are the main cell type of breast cancer microenvironment and can represent up to 80% of the tumor mass. In particular, BCAFs induce cancer initiation, proliferation, invasion and metastasis by undergoing an activation process associated with the secretion of growth factors, cytokines, and paracrine interactions. Therapy resistance is the main cause of poor therapeutic results or even failure in breast cancer patients. Despite recent advances in breast cancer management, there is a need for new prognostic markers and novel agents for targeting key signalling pathways to either improve the efficacy of the current therapies, or reduce toxicity. In this view, BCAFs represent markers useful to clinical diagnosis, therapy, and prognosis of breast cancer. This review focuses on the role of BCAFs in cancer, and describes the processes of endocrine/chemotherapy resistance linked to BCAFs action. Moreover, it points to molecules and pathways regulating therapy resistance induced by BCAFs. Finally, potential therapeutic strategies targeting BCAFs and offering new tools in breast cancer therapy are highlighted.

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MicroRNA Expression Profiles and Breast Cancer Chemotherapy

International Journal of Molecular Sciences ◽

10.3390/ijms221910812 ◽

2021 ◽

Vol 22 (19) ◽

pp. 10812

Author(s):

Matthew G. Davey ◽

Aoife J. Lowery ◽

Nicola Miller ◽

Michael J. Kerin

Keyword(s):

Breast Cancer ◽

Expression Profiles ◽

Therapeutic Strategies ◽

Cytotoxic Agents ◽

Surgical Approaches ◽

Activity Measurement ◽

Breast Cancer Patients ◽

Curative Intent ◽

Breast Cancer Chemotherapy ◽

Cancer Management

Breast cancer is the most common malignancy diagnosed in women. Traditionally, radical surgical resection was the cornerstone of breast cancer management, with limited exceptions. In recent times, our enhanced appreciation of the biomolecular characteristics of breast cancer has transformed the treatment paradigm to include prescription of chemotherapeutical agents, radiotherapies, targeted therapies, as well as more refined surgical approaches. While treatments with such modalities have enhanced clinico-oncological outcomes for breast cancer patients, the efforts of oncological and translational research have concentrated on the identification of novel biomarkers which may successfully inform prognosis and response to therapies, improve current therapeutic strategies, and enhance prognostication. Mi(cro)RNAs are small, non-coding molecules which are known to play regulatory roles in governing gene expression and cellular activity. Measurement of miRNA expression profiles have been illustrated to inform the response to therapies, such as conventional chemotherapy, and are currently undergoing assessment as means of enhancing treatment strategies with these cytotoxic agents. Herein, this review outlines how chemotherapy prescription has revolutionised breast cancer treatment and illustrates the novel role of miRNAs as biomarkers capable of enhancing current therapeutic strategies using chemotherapy in patients being treated with curative intent for breast cancer.

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

Biomedicines ◽

10.3390/biomedicines9121921 ◽

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.

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Investigating New Therapeutic Strategies Targeting Hyperinsulinemia's Mitogenic Effects in a Female Mouse Breast Cancer Model

Endocrinology ◽

10.1210/en.2012-2263 ◽

2013 ◽

Vol 154 (5) ◽

pp. 1701-1710 ◽

Cited By ~ 21

Author(s):

Ran Rostoker ◽

Keren Bitton-Worms ◽

Avishay Caspi ◽

Zila Shen-Orr ◽

Derek LeRoith

Keyword(s):

Breast Cancer ◽

Tumor Growth ◽

Breast Tumor ◽

Experimental Studies ◽

Tumor Development ◽

Treated Group ◽

Tumor Growth Rate ◽

Breast Cancer Patients ◽

Mitogenic Effect

Abstract Epidemiological and experimental studies have identified hyperinsulinemia as an important risk factor for breast cancer induction and for the poor prognosis in breast cancer patients with obesity and type 2 diabetes. Recently it was demonstrated that both the insulin receptor (IR) and the IGF-IR mediate hyperinsulinemia's mitogenic effect in several breast cancer models. Although IGF-IR has been intensively investigated, and anti-IGF-IR therapies are now in advanced clinical trials, the role of the IR in mediating hyperinsulinemia's mitogenic effect remains to be clarified. Here we aimed to explore the potential of IR inhibition compared to dual IR/IGF-IR blockade on breast tumor growth. To initiate breast tumors, we inoculated the mammary carcinoma Mvt-1 cell line into the inguinal mammary fat pad of the hyperinsulinemic MKR female mice, and to study the role of IR, we treated the mice bearing tumors with the recently reported high-affinity IR antagonist-S961, in addition to the well-documented IGF-IR inhibitor picropodophyllin (PPP). Although reducing IR activation, with resultant severe hyperglycemia and hyperinsulinemia, S961-treated mice had significantly larger tumors compared to the vehicle-treated group. This effect maybe secondary to the severe hyperinsulinemia mediated via the IGF-1 receptor. In contrast, PPP by partially inhibiting both IR and IGF-IR activity reduced tumor growth rate with only mild metabolic consequences. We conclude that targeting (even partially) both IR and IGF-IRs impairs hyperinsulinemia's effects in breast tumor development while simultaneously sparing the metabolic abnormalities observed when targeting IR alone with virtual complete inhibition.

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Exosomes: A Forthcoming Era of Breast Cancer Therapeutics

Cancers ◽

10.3390/cancers13184672 ◽

2021 ◽

Vol 13 (18) ◽

pp. 4672

Author(s):

Banashree Bondhopadhyay ◽

Sandeep Sisodiya ◽

Faisal Abdulrahman Alzahrani ◽

Muhammed A. Bakhrebah ◽

Atul Chikara ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Therapeutics ◽

Therapeutic Strategies ◽

Breast Cancer Patients ◽

Liquid Biopsies ◽

Non Invasive ◽

Tumor Tissues ◽

Circulating Markers

Despite the recent advancements in therapeutics and personalized medicine, breast cancer remains one of the most lethal cancers among women. The prognostic and diagnostic aids mainly include assessment of tumor tissues with conventional methods towards better therapeutic strategies. However, current era of gene-based research may influence the treatment outcome particularly as an adjunct to diagnostics by exploring the role of non-invasive liquid biopsies or circulating markers. The characterization of tumor milieu for physiological fluids has been central to identifying the role of exosomes or small extracellular vesicles (sEVs). These exosomes provide necessary communication between tumor cells in the tumor microenvironment (TME). The manipulation of exosomes in TME may provide promising diagnostic/therapeutic strategies, particularly in triple-negative breast cancer patients. This review has described and highlighted the role of exosomes in breast carcinogenesis and how they could be used or targeted by recent immunotherapeutics to achieve promising intervention strategies.

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Getting It Wrong Most of The Time: Comparing Trialists’ Choice of Primary Outcome With What Patients And Health Professionals Want

10.21203/rs.3.rs-1084868/v1 ◽

2021 ◽

Author(s):

Shaun Treweek ◽

Viviane Miyakoda ◽

Dylan Burke ◽

Frances Shiely

Keyword(s):

Breast Cancer ◽

Decision Making ◽

Health Care Professionals ◽

Primary Outcome ◽

Healthcare Professionals ◽

Breast Cancer Patients ◽

Additional Information ◽

Cancer Management ◽

Breast Cancer Management ◽

Secondary Outcomes

Abstract Background: Randomised trials support improved decision-making through the data they collect. One important piece of data is the primary outcome – so called because it is what the investigators decide is the most important. Secondary outcomes provide additional information to support decision-making. We were interested in knowing how important patients and healthcare professionals consider the outcomes (especially the primary outcome) measured in a selection of published trials. Methods: The work had three stages: 1. We identified a body of late-stage trials in two clinical areas, breast cancer management and nephrology. 2. We identified the primary and secondary outcomes for these trials. 3. We randomly ordered these outcomes and presented them to patients and healthcare professionals (with experience of the clinical area), and we asked them to rank the importance of the outcomes. They were not told which outcomes trial authors considered primary and secondary. Results: In our sample of 44 trials with 46 primary outcomes, 29 patients, one patient representative and 12 healthcare professionals together ranked the primary outcome as the most important outcome 13/46 times, or 30%. Breast cancer patients and health care professionals considered the primary outcome to be the most important outcome for 8/21 primary outcomes chosen by trialists. For nephrology, the equivalent figure was 5/25. The primary outcome appeared in a respondent’s top 5 ranked outcomes 151/178 (85%) times for breast cancer and 225/259 (87%) times for nephrology even if the primary wasn’t considered the most important outcome. Conclusions: The primary outcome in a trial is the most important piece of data collected. It is used to determine how many participants are required, and it is the main piece of information used to judge whether the intervention is effective or not. Our study found that in the view of patients and healthcare professionals, teams doing trials in breast cancer management and nephrology got their choice of primary outcome wrong 70% of the time.

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Suggested modifications in the management of breast cancer patients in the era of COVID-19 pandemic: a web-based survey. (Preprint)

10.2196/preprints.27073 ◽

2021 ◽

Author(s):

Shereef Elsamany ◽

Mohamed Elbaiomy ◽

Ahmed Zeeneldin ◽

Emad Tashkandi ◽

Fayza Hassanin ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

United Arab Emirates ◽

Hormonal Therapy ◽

Breast Cancer Patients ◽

Her2 Positive ◽

Web Based ◽

Cancer Management ◽

Breast Cancer Management ◽

Positive Breast Cancer

BACKGROUND Management of cancer patients in the current era of COVID-19 pandemic poses a significant challenge on health care systems. OBJECTIVE We explored the views of oncologists for the management of breast cancer patients during COVID-19 pandemic. METHODS A web-based questionnaire using SurveyMonkey was submitted to licensed oncologists involved in breast cancer management in Saudi Arabia, Egypt and United Arab Emirates. The survey focused on characteristics of participants, infection risk among cancer patients and possible treatment modifications related to different types of breast cancer RESULTS The survey was completed by 82 participants. For early HR positive, HER2-negative breast cancer,74.4% supported using neoadjuvant hormonal therapy in selected patients, and 58.0% preferred giving 6 over 8 cycles of adjuvant chemotherapy when indicated. Only 42.7% preferred CDK4/6 inhibitor with hormonal therapy as first line in all patients with metastatic HR-positive disease. 67.1% of participants supported using adjuvant trastuzumab for 6 instead of 12 months in selected patients with HER2-positive breast cancer. For metastatic HER2-positive, HR-positive breast cancer, 80.5% of participants supported the use of hormonal therapy with dual anti-HER2 blockade in selected patients. The preferred choice of 1st line treatment in metastatic triple negative patients with BRCA mutation and PDL1<1%, was PARP inhibitor according to 42.5% of the participants, and atezolizumab with nabpaclitaxel if the PDL1>1% according to 70.4% of the participants. CONCLUSIONS Several modifications in breast cancer management is supported by the survey participants. These modifications need to be discussed on local basis taking into account the local infrastructure and available resources. CLINICALTRIAL none

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Blockade of CDK7 Reverses Endocrine Therapy Resistance in Breast Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms21082974 ◽

2020 ◽

Vol 21 (8) ◽

pp. 2974 ◽

Cited By ~ 2

Author(s):

Yasmin M. Attia ◽

Samia A. Shouman ◽

Salama A. Salama ◽

Cristina Ivan ◽

Abdelrahman M. Elsayed ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Volume ◽

Apoptotic Cell ◽

Therapy Resistance ◽

Tamoxifen Treatment ◽

Clinical Samples ◽

Breast Cancer Cell Lines ◽

Breast Cancer Patients

Cyclin-dependent kinase (CDK)-7 inhibitors are emerging as promising drugs for the treatment of different types of cancer that show chemotherapy resistance. Evaluation of the effects of CDK7 inhibitor, THZ1, alone and combined with tamoxifen is of paramount importance. Thus, in the current work, we assessed the effects of THZ1 and/or tamoxifen in two estrogen receptor-positive (ER+) breast cancer cell lines (MCF7) and its tamoxifen resistant counterpart (LCC2) in vitro and in xenograft mouse models of breast cancer. Furthermore, we evaluated the expression of CDK7 in clinical samples from breast cancer patients. Cell viability, apoptosis, and genes involved in cell cycle regulation and tamoxifen resistance were determined. Tumor volume and weight, proliferation marker (Ki67), angiogenic marker (CD31), and apoptotic markers were assayed. Bioinformatic data indicated CDK7 expression was associated with negative prognosis, enhanced pro-oncogenic pathways, and decreased response to tamoxifen. Treatment with THZ1 enhanced tamoxifen-induced cytotoxicity, while it inhibited genes involved in tumor progression in MCF-7 and LCC2 cells. In vivo, THZ1 boosted the effect of tamoxifen on tumor weight and tumor volume, reduced Ki67 and CD31 expression, and increased apoptotic cell death. Our findings identify CDK7 as a possible therapeutic target for breast cancer whether it is sensitive or resistant to tamoxifen therapy.

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The Primary Cilium of Adipose Progenitors Is Necessary for Their Differentiation into Cancer-Associated Fibroblasts that Promote Migration of Breast Cancer Cells In Vitro

Cells ◽

10.3390/cells9102251 ◽

2020 ◽

Vol 9 (10) ◽

pp. 2251

Author(s):

Pascal Peraldi ◽

Annie Ladoux ◽

Sophie Giorgetti-Peraldi ◽

Christian Dani

Keyword(s):

Breast Cancer ◽

Primary Cilium ◽

Biological Effects ◽

Tumor Development ◽

Breast Cancer Cell Lines ◽

Cancer Associated Fibroblasts ◽

Central Elements ◽

Control Tumor ◽

Tgf Β1

Cancer associated fibroblasts (CAFs) are central elements of the microenvironment that control tumor development. In breast cancer, CAFs can originate from adipose progenitors (APs). We, and others, have shown that the primary cilium, an antenna-shaped organelle, controls several aspects of APs’ biology. We studied the conversion of human APs into CAFs by breast cancer cell lines (BCCs). Deletion of the cilium of APs by a pharmacological inhibitor, or by siRNA, allow us to demonstrate that the cilium is necessary for the differentiation of APs into CAFs. BCCs increase production of TGF-β1 by APs, which is a known inducer of CAFs. Pharmacological inhibition of TGF-β1 signaling in APs prevents their conversion into CAFs. Since we previously showed that deletion of the APs’ cilium inhibits TGF-β1 signaling, we propose that BCCs induce TGF-β1 production in Aps, which binds to the primary cilium of Aps and leads to their differentiation into CAFs. Inhibition of APs conversion into CAFs induces a loss in some of the biological effects of CAFs since deletion of the cilium of APs decreases their effect on the migration of BCCs. This is the first observation of a function of the cilium of APs in their conversion into CAFs, and its consequences on BCCs.

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Micropallet Technology for Investigating Tumor Cellular Profiles and Analysis of Rare Cell Subsets

ASME 2008 3rd Frontiers in Biomedical Devices Conference ◽

10.1115/biomed2008-38058 ◽

2008 ◽

Author(s):

Nicholas M. Gunn ◽

Mark Bachman ◽

Edward L. Nelson ◽

G.-P. Li

Keyword(s):

Breast Cancer ◽

United States ◽

Cancer Patients ◽

Invasive Breast Cancer ◽

Breast Tumor ◽

The United States ◽

Therapeutic Strategies ◽

Cellular Heterogeneity ◽

Breast Cancer Patients ◽

Critical Limits

Rationally designed, individualized therapeutic strategies have long been a desired objective for breast cancer patients and clinicians as an estimated 178,480 new cases of invasive breast cancer will be diagnosed among women in the United States this year and over 40,000 women are expected to die from the disease. [1] The increasing appreciation of breast tumor cellular heterogeneity raises fundamental questions as to the relative contributions of cellular subsets to the biologic behavior of an individual patient’s tumor. [2] As such, it has become increasingly clear that in many cases, an individualized strategy for the treatment of breast cancer would be of great benefit, and that the ability to isolate relevant cellular subsets from the main tumor population is one of the critical limits to accomplishing this goal.

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Bilateral breast cancer: a case study

Journal of Radiotherapy in Practice ◽

10.1017/s1460396919000761 ◽

2019 ◽

Vol 19 (3) ◽

pp. 305-308

Author(s):

Rajanigandha Tudu ◽

Anup Kumar ◽

Rashmi Singh ◽

Payal Raina

Keyword(s):

Breast Cancer ◽

Primary Breast Cancer ◽

Breast Cancer Incidence ◽

Bilateral Breast Cancer ◽

Late Presentation ◽

Incidence Rates ◽

Breast Cancers ◽

Breast Cancer Patients ◽

Screening Guidelines ◽

Cancer Management

AbstractBackground:Breast cancer is the most common cancer among females worldwide. Increasing breast cancer incidence rates, improved diagnosis and management modalities and growing life expectancy have resulted in increasing numbers of women at risk of developing contralateral primary breast cancer. Bilateral breast cancer can occur synchronously or metachronously.Material and methods:This study reports three cases of bilateral breast cancer patients treated at our oncology department between March 2018 and March 2019. The features of presentation, investigation, diagnosis and follow-up care are the highlights of this study.Results:Bilateral breast cancer was noted in three patients among the study population in the age group of 35 –55 years. Two of these patients had metachronous bilateral breast cancer, and one patient developed cancer in the second breast during the course of management. The second breast cancers differed histologically from primary breast cancer.Conclusion:Poor awareness on breast cancer care and the lack of national screening guidelines and programmes, and poor infrastructure, all contribute to late presentation and difficult breast cancer management. Proper history, clinical examination and imaging of opposite breast should be done to ensure adequate and timely management of bilateral breast cancer.

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