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Breast Development and Cancer

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Survivorship and Quality of Life".

Deadline for manuscript submissions: closed (25 July 2022) | Viewed by 41472

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Prof. Dr. Martine Berliere

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Department of Gynecology, Breast Clinic, King Albert II Institute, Cliniques universitaires Saint-Luc, UCLouvain, 1200 Brussels, Belgium
Interests: breast cancer; oncologic breast surgery; post surgery persistent pain syndrome side effects of anticancer treatments; hypnosis sedation; breast cancer recurrence; genomics; inflammation and cancer; fertility preservation and breast cancer; endocrine therapy and breast cancer; mechanismes of endocrine resistance; in situ ductal carcinoma; breast cancer progression; integrative oncology
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Prof. Christine C. Galant

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Department of Pathology, Cliniques universitaires Saint-Luc Bruxelles, 1200 Brussels, Belgium
Interests: breast carcinoma; invasive; ductal; lobular; spécial types; in situ; papillar; stroma; cytology; biopsy; resection specimen; decalcification; immunohistochemistry; receptor; ER; PR; Ki67; HER2; digital pathology; molecular analysis; mutation; fusion genes

Special Issue Information

Dear Colleagues,

Breast development is a complex process: breasts undergo multiple changes throughout life, from the intrauterine life to senescence. The human breast consists of parenchymal and stromal elements. The parenchyme forms a system of branching ducts eventually leading to secretory acini development, and the stroma consists mainly of adipose tissue, providing the environment for the development of parenchyma; mutual and reciprocal interactions between epithelial components and mesenchymal or stromal cells are responsible for prenatal, infant and pubertal breast development. Evidence suggests that the mesenchyme has indictive properties that lead to the local migration and changes in the cell adhesion of epithelial cells. Hormonal influences on this paracrine interaction between the mesenchyme and parenchyme are evident at all stages of development. The formation of lactiferous ducts is induced by placental hormones entering the foetal circulation; other implicated hormones are progesterone, growth hormone, insulin-like growth factor, oestrogens, prolactin, adrenal corticoids and triidothyronine.

Mammary stem cells and progenitors do not express receptors for hormones, and hormone-positive cells generally do not proliferate.

The microenvironment plays an important role in tissue homeostasis, cancer progression and metastasis.

To fully understand the defects leading to breast cancer, it is essential to decipher the mechanisms that regulate normal mammary development and morphogenesis.

Despite the considerable headway made in the field, our outstanding of the complex cascade of signals between neighbouring cells of developing tissues and the role of the matrix microenvironment is still largely lacking.

Moreover, the same general processes, from proliferation to invasion, which take place during normal mammary development, also occur in malignant disease.

The identification of mechanisms and genes that govern stem and progenitor cell expansion, or that determine daughter cell fate, will be of crucial interest for understanding breast cancer diversity and ultimately improving treatment options.

Prof. Dr. Martine Berliere
Prof. Christine C. Galant
Guest Editors

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Keywords

breast development
breast cancer
interactions between stroma and epithelial cells
hormone receptors
stem cells
progenitors

Published Papers (10 papers)

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Editorial

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3 pages, 179 KiB

Open AccessEditorial

Breast Development and Cancer

by Martine Berliere, Francois P. Duhoux, Aline François and Christine Galant

Cancers 2023, 15(6), 1731; https://doi.org/10.3390/cancers15061731 - 13 Mar 2023

Viewed by 1133

Abstract

The human breast, as mentioned by Gudjonsson and co-authors [...] Full article

(This article belongs to the Special Issue Breast Development and Cancer)

Research

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21 pages, 2532 KiB

Open AccessArticle

Sabizabulin, a Potent Orally Bioavailable Colchicine Binding Site Agent, Suppresses HER2+ Breast Cancer and Metastasis

by Raisa I. Krutilina, Kelli L. Hartman, Damilola Oluwalana, Hilaire C. Playa, Deanna N. Parke, Hao Chen, Duane D. Miller, Wei Li and Tiffany N. Seagroves

Cancers 2022, 14(21), 5336; https://doi.org/10.3390/cancers14215336 - 29 Oct 2022

Cited by 8 | Viewed by 3542

Abstract

HER2+ breast cancer accounts for 15% of all breast cancer cases. Current frontline therapy for HER2+ metastatic breast cancer relies on targeted antibodies, trastuzumab and pertuzumab, combined with microtubule inhibitors in the taxane class (paclitaxel or docetaxel). It is well known that the clinical efficacy of taxanes is limited by the development of chemoresistance and hematological and neurotoxicities. The colchicine-binding site inhibitors (CBSIs) are a class of promising alternative agents to taxane therapy. Sabizabulin (formerly known as VERU-111) is a potent CBSI that overcomes P-gp-mediated taxane resistance, is orally bioavailable, and inhibits tumor growth and distant metastasis in triple negative breast cancer (TNBC). Herein, we demonstrate the efficacy of sabizabulin in HER2⁺ breast cancer. In vitro, sabizabulin inhibits the proliferation of HER2+ breast cancer cell lines with low nanomolar IC₅₀ values, inhibits clonogenicity, and induces apoptosis in a concentration-dependent manner. In vivo, sabizabulin inhibits breast tumor growth in the BT474 (ER+/PR+/HER2+) xenograft model and a HER2+ (ER-/PR-) metastatic patient-derived xenograft (PDX) model, HCI-12. We demonstrate that sabizabulin is a promising alternative agent to target tubulin in HER2+ breast cancer with similar anti-metastatic efficacy to paclitaxel, but with the advantage of oral bioavailability and lower toxicity than taxanes. Full article

(This article belongs to the Special Issue Breast Development and Cancer)

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16 pages, 3661 KiB

Open AccessArticle

The Histone Demethylase HR Suppresses Breast Cancer Development through Enhanced CELF2 Tumor Suppressor Activity

by Yao Shen, Jasvinder Singh, Bindeshwar Sah, Zhongming Chen, Wootae Ha, Christine Henzler, Tao Su, Lillian Xie, Yibin Deng, Gen Li, Hua Guo, Hanina Hibshoosh and Liang Liu

Cancers 2022, 14(19), 4648; https://doi.org/10.3390/cancers14194648 - 24 Sep 2022

Cited by 2 | Viewed by 1683

Abstract

The hairless (HR) gene encodes a transcription factor with histone demethylase activity that is essential for development and tissue homeostasis. Previous studies suggest that mutational inactivation of HR promotes tumorigenesis. To investigate HR mutations in breast cancer, we performed targeted next-generation sequencing using DNA isolated from primary breast cancer tissues. We identified HR somatic mutations in approximately 15% of the patient cohort (n = 85), compared with 23% for BRCA2, 13% for GATA3, 7% for BRCA1, and 3% for PTEN in the same patient cohort. We also found an average 23% HR copy number loss in breast cancers. In support of HR’s antitumor functions, HR reconstitution in HR-deficient human breast cancer cells significantly suppressed tumor growth in orthotopic xenograft mouse models. We further demonstrated that HR’s antitumor activity was at least partly mediated by transcriptional activation of CELF2, a tumor suppressor with RNA-binding activity. Consistent with HR’s histone demethylase activity, pharmacologic inhibition of histone methylation suppressed HR-deficient breast cancer cell proliferation, migration and tumor growth. Taken together, we identified HR as a novel tumor suppressor that is frequently mutated in breast cancer. We also showed that pharmacologic inhibition of histone methylation is effective in suppressing HR-deficient breast tumor growth and progression. Full article

(This article belongs to the Special Issue Breast Development and Cancer)

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14 pages, 900 KiB

Open AccessEditor’s ChoiceArticle

Accurate Screening for Early-Stage Breast Cancer by Detection and Profiling of Circulating Tumor Cells

by Timothy Crook, Robert Leonard, Kefah Mokbel, Alastair Thompson, Michael Michell, Raymond Page, Ashok Vaid, Ravi Mehrotra, Anantbhushan Ranade, Sewanti Limaye, Darshana Patil, Dadasaheb Akolkar, Vineet Datta, Pradip Fulmali, Sachin Apurwa, Stefan Schuster, Ajay Srinivasan and Rajan Datar

Cancers 2022, 14(14), 3341; https://doi.org/10.3390/cancers14143341 - 9 Jul 2022

Cited by 20 | Viewed by 9054

Abstract

Background: The early detection of breast cancer (BrC) is associated with improved survival. We describe a blood-based breast cancer detection test based on functional enrichment of breast-adenocarcinoma-associated circulating tumor cells (BrAD-CTCs) and their identification via multiplexed fluorescence immunocytochemistry (ICC) profiling for GCDFP15, GATA3, EpCAM, PanCK, and CD45 status. Methods: The ability of the test to differentiate BrC cases (N = 548) from healthy women (N = 9632) was evaluated in a case–control clinical study. The ability of the test to differentiate BrC cases from those with benign breast conditions was evaluated in a prospective clinical study of women (N = 141) suspected of BrC. Results: The test accurately detects BrAD-CTCs in breast cancers, irrespective of age, ethnicity, disease stage, grade, or hormone receptor status. Analytical validation established the high accuracy and reliability of the test under intended use conditions. The test detects and differentiates BrC cases from healthy women with 100% specificity and 92.07% overall sensitivity in a case–control study. In a prospective clinical study, the test shows 93.1% specificity and 94.64% overall sensitivity in differentiating breast cancer cases (N = 112) from benign breast conditions (N = 29). Conclusion: The findings reported in this manuscript support the clinical potential of this test for blood-based BrC detection. Full article

(This article belongs to the Special Issue Breast Development and Cancer)

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18 pages, 4605 KiB

Open AccessArticle

Targeted Deletion of Kindlin-2 in Mouse Mammary Glands Inhibits Tumor Growth, Invasion, and Metastasis Downstream of a TGF-β/EGF Oncogenic Signaling Pathway

by Wei Wang, Priyanka S. Rana, Akram Alkrekshi, Katarzyna Bialkowska, Vesna Markovic, William P. Schiemann, Edward F. Plow, Elzbieta Pluskota and Khalid Sossey-Alaoui

Cancers 2022, 14(3), 639; https://doi.org/10.3390/cancers14030639 - 27 Jan 2022

Cited by 5 | Viewed by 3038

Abstract

Breast cancer (BC) is one of the leading causes of cancer-related deaths due in part to its invasive and metastatic properties. Kindlin-2 (FERMT2) is associated with the pathogenesis of several cancers. Although the role of Kindlin-2 in regulating the invasion-metastasis cascade in BC is widely documented, its function in BC initiation and progression remains to be fully elucidated. Accordingly, we generated a floxed mouse strain by targeting the Fermt2 (K2^lox/lox) locus, followed by tissue-specific deletion of Kindlin-2 in the myoepithelial compartment of the mammary glands by crossing the K2^lox/lox mice with K14-Cre mice. Loss of Kindlin-2 in mammary epithelial cells (MECs) showed no deleterious effects on mammary gland development, fertility, and lactation in mice bearing Kindlin-2-deletion. However, in a syngeneic mouse model of BC, mammary gland, specific knockout of Kindlin-2 inhibited the growth and metastasis of murine E0771 BC cells inoculated into the mammary fat pads. However, injecting the E0771 cells into the lateral tail vein of Kindlin-2-deleted mice had no effect on tumor colonization in the lungs, thereby establishing a critical role of MEC Kindlin-2 in supporting BC tumor growth and metastasis. Mechanistically, we found the MEC Kindlin-2-mediated inhibition of tumor growth and metastasis is accomplished through its regulation of the TGF-β/ERK MAP kinase signaling axis. Thus, Kindlin-2 within the mammary gland microenvironment facilitates the progression and metastasis of BC. Full article

(This article belongs to the Special Issue Breast Development and Cancer)

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19 pages, 2504 KiB

Open AccessArticle

YB1 Is a Major Contributor to Health Disparities in Triple Negative Breast Cancer

by Priyanka Shailendra Rana, Wei Wang, Akram Alkrekshi, Vesna Markovic, Amer Khiyami, Ricky Chan, Adam Perzynski, Natalie Joseph and Khalid Sossey-Alaoui

Cancers 2021, 13(24), 6262; https://doi.org/10.3390/cancers13246262 - 14 Dec 2021

Cited by 6 | Viewed by 3044

Abstract

Triple negative breast cancer (TNBC) is the most aggressive amongst all breast cancer (BC) subtypes. While TNBC tumors represent less than 20% of all BC subtypes, they are responsible for the most BC-related deaths. More significantly, when considering TNBC incidence across all racial/ethnic groups, TNBC accounts for less than 20% of all BCs. However, in non-Hispanic black women, the incidence rate of TNBC is more than 40%, which may be a contributing factor to the higher BC-related death rate in this population. These disparities remain strong even after accounting for differences in socioeconomic status, healthcare access, and lifestyle factors. Increased evidence now points to biological mechanisms that are intrinsic to the tumor that contribute to disparate TNBC disease burdens. Here, we show that YB1, a multifunction gene, plays a major role in the TNBC disparities between African American (AA) and Caucasian American (CA) women. We show in three independent TNBC tumors cohorts, that YB1 is significantly highly expressed in AA TNBC tumors when compared to CAs, and that increased levels of YB1 correlate with poor survival of AA patients with TNBC. We used a combination of genetic manipulation of YB1 and chemotherapy treatment, both in vitro and in animal models of TNBC to show that YB1 oncogenic activity is more enhanced in TNBC cell lines of AA origin, by increasing their tumorigenic and aggressive behaviors, trough the activation of cancer stem cell phenotype and resistance to chemotherapeutic treatments. Full article

(This article belongs to the Special Issue Breast Development and Cancer)

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20 pages, 3014 KiB

Open AccessArticle

Anthocyanidins Inhibit Growth and Chemosensitize Triple-Negative Breast Cancer via the NF-κB Signaling Pathway

by Farrukh Aqil, Radha Munagala, Ashish K. Agrawal, Jeyaprakash Jeyabalan, Neha Tyagi, Shesh N. Rai and Ramesh C. Gupta

Cancers 2021, 13(24), 6248; https://doi.org/10.3390/cancers13246248 - 13 Dec 2021

Cited by 9 | Viewed by 2482

Abstract

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer. Due to the lack of drug-targetable receptors, chemotherapy is the only systemic treatment option. Although chemotherapeutic drugs respond initially in TNBC, many patients relapse and have a poor prognosis. Poor survival after metastatic relapse is largely attributed to the development of resistance to chemotherapeutic drugs. In this study, we show that bilberry-derived anthocyanidins (Anthos) can inhibit the growth and metastasis of TNBC and chemosensitize paclitaxel (PAC)-resistant TNBC cells by modulating the NF-κB signaling pathway, as well as metastatic and angiogenic mediators. Anthos administered orally significantly decreased MDA-MB-231 orthoxenograft tumor volume and led to lower rates of lymph node and lung metastasis, compared to control. Treatment of PAC-resistant MDA-MB-231Tx cells with Anthos and PAC in combination lowered the IC₅₀ of PAC by nearly 20-fold. The combination treatment also significantly (p < 0.01) decreased the tumor volume in MDA-MB-231Tx orthoxenografts, compared to control. In contrast, Anthos and PAC alone were ineffective against MDA-MB-231Tx tumors. Our approach of using Anthos to inhibit the growth and metastasis of breast cancers, as well as to chemosensitize PAC-resistant TNBC, provides a highly promising and effective strategy for the management of TNBC. Full article

(This article belongs to the Special Issue Breast Development and Cancer)

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Review

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15 pages, 7282 KiB

Open AccessReview

Effects of Hormones on Breast Development and Breast Cancer Risk in Transgender Women

by Martine Berliere, Maximilienne Coche, Camille Lacroix, Julia Riggi, Maude Coyette, Julien Coulie, Christine Galant, Latifa Fellah, Isabelle Leconte, Dominique Maiter, Francois P. Duhoux and Aline François

Cancers 2023, 15(1), 245; https://doi.org/10.3390/cancers15010245 - 30 Dec 2022

Cited by 5 | Viewed by 10040

Abstract

Transgender women experience gender dysphoria due to a gender assignment at birth that is incongruent with their gender identity. Transgender people undergo different surgical procedures and receive sex steroids hormones to reduce psychological distress and to induce and maintain desired physical changes. These persons on feminizing hormones represent a unique population to study the hormonal effects on breast development, to evaluate the risk of breast cancer and perhaps to better understand the precise role played by different hormonal components. In MTF (male to female) patients, hormonal treatment usually consists of antiandrogens and estrogens. Exogenous hormones induce breast development with the formation of ducts and lobules and an increase in the deposition of fat. A search of the existing literature dedicated to hormone regimens for MTF patients, their impact on breast tissue (incidence and type of breast lesions) and breast cancer risk provided the available information for this review. The evaluation of breast cancer risk is currently complicated by the heterogeneity of administered treatments and a lack of long-term follow-up in the great majority of studies. Large studies with longer follow-up are required to better evaluate the breast cancer risk and to understand the precise mechanisms on breast development of each exogenous hormone. Full article

(This article belongs to the Special Issue Breast Development and Cancer)

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11 pages, 16327 KiB

Open AccessReview

Cellular Plasticity and Heterotypic Interactions during Breast Morphogenesis and Cancer Initiation

by Saevar Ingthorsson, Gunnhildur Asta Traustadottir and Thorarinn Gudjonsson

Cancers 2022, 14(21), 5209; https://doi.org/10.3390/cancers14215209 - 24 Oct 2022

Cited by 3 | Viewed by 1867

Abstract

The human breast gland is a unique organ as most of its development occurs postnatally between menarche and menopause, a period ranging from 30 to 40 years. During this period, the monthly menstruation cycle drives the mammary gland through phases of cell proliferation, differentiation, and apoptosis, facilitated via a closely choreographed interaction between the epithelial cells and the surrounding stroma preparing the gland for pregnancy. If pregnancy occurs, maximal differentiation is reached to prepare for lactation. After lactation, the mammary gland involutes to a pre-pregnant state. These cycles of proliferation, differentiation, and involution necessitate the presence of epithelial stem cells that give rise to progenitor cells which differentiate further into the luminal and myoepithelial lineages that constitute the epithelial compartment and are responsible for the branching structure of the gland. Maintaining homeostasis and the stem cell niche depends strongly on signaling between the stem and progenitor cells and the surrounding stroma. Breast cancer is a slowly progressing disease whose initiation can take decades to progress into an invasive form. Accumulating evidence indicates that stem cells and/or progenitor cells at different stages, rather than terminally differentiated cells are the main cells of origin for most breast cancer subgroups. Stem cells and cancer cells share several similarities such as increased survival and cellular plasticity which is reflected in their ability to switch fate by receiving intrinsic and extrinsic signals. In this review, we discuss the concept of cellular plasticity in normal breast morphogenesis and cancer, and how the stromal environment plays a vital role in cancer initiation and progression. Full article

(This article belongs to the Special Issue Breast Development and Cancer)

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19 pages, 1281 KiB

Open AccessReview

The Role of Interstitial Brachytherapy for Breast Cancer Treatment: An Overview of Indications, Applications, and Technical Notes

by Salvatore Cozzi, Matteo Augugliaro, Patrizia Ciammella, Andrea Botti, Valeria Trojani, Masoumeh Najafi, Gladys Blandino, Maria Paola Ruggieri, Lucia Giaccherini, Emanuele Alì, Federico Iori, Angela Sardaro, Sebastiano Finocchi Ghersi, Letizia Deantonio, Cristina Gutierrez Miguelez, Cinzia Iotti and Lilia Bardoscia

Cancers 2022, 14(10), 2564; https://doi.org/10.3390/cancers14102564 - 23 May 2022

Cited by 9 | Viewed by 4591

Abstract

Breast cancer represents the second leading cause of cancer-related death in the female population, despite continuing advances in treatment options that have significantly accelerated in recent years. Conservative treatments have radically changed the concept of healing, also focusing on the psychological aspect of oncological treatments. In this scenario, radiotherapy plays a key role. Brachytherapy is an extremely versatile radiation technique that can be used in various settings for breast cancer treatment. Although it is invasive, technically complex, and requires a long learning curve, the dosimetric advantages and sparing of organs at risk are unequivocal. Literature data support muticatheter interstitial brachytherapy as the only method with strong scientific evidence to perform partial breast irradiation and reirradiation after previous conservative surgery and external beam radiotherapy, with longer follow-up than new, emerging radiation techniques, whose effectiveness is proven by over 20 years of experience. The aim of our work is to provide a comprehensive view of the use of interstitial brachytherapy to perform breast lumpectomy boost, breast-conserving accelerated partial breast irradiation, and salvage reirradiation for ipsilateral breast recurrence, with particular focus on the implant description, limits, and advantages of the technique. Full article

(This article belongs to the Special Issue Breast Development and Cancer)

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