-
International Journal of Molecular... Dec 2021Breast cancer prevention is a major challenge worldwide. During the last few years, efforts have been made to identify molecular breast tissue factors that could be... (Review)
Review
Breast cancer prevention is a major challenge worldwide. During the last few years, efforts have been made to identify molecular breast tissue factors that could be linked to an increased risk of developing the disease in healthy women. In this concern, steroid hormones and their receptors are key players since they are deeply involved in the growth, development and lifetime changes of the mammary gland and play a crucial role in breast cancer development and progression. In particular, androgens, by binding their own receptor, seem to exert a dichotomous effect, as they reduce cell proliferation in estrogen receptor α positive (ERα+) breast cancers while promoting tumour growth in the ERα negative ones. Despite this intricate role in cancer, very little is known about the impact of androgen receptor (AR)-mediated signalling on normal breast tissue and its correlation to breast cancer risk factors. Through an accurate collection of experimental and epidemiological studies, this review aims to elucidate whether androgens might influence the susceptibility for breast cancer. Moreover, the possibility to exploit the AR as a useful marker to predict the disease will be also evaluated.
Topics: Androgens; Breast Neoplasms; Disease Susceptibility; Female; Humans; Mammary Glands, Human; Receptors, Androgen; Risk Factors
PubMed: 35008851
DOI: 10.3390/ijms23010424 -
Journal of Mammary Gland Biology and... Jun 2010Activation of the ErbB family of receptor tyrosine kinases via cognate Epidermal Growth Factor (EGF)-like peptide ligands constitutes a major group of related signaling... (Review)
Review
Activation of the ErbB family of receptor tyrosine kinases via cognate Epidermal Growth Factor (EGF)-like peptide ligands constitutes a major group of related signaling pathways that control proliferation, survival, angiogenesis and metastasis of breast cancer. In this respect, clinical trials with various ErbB receptor blocking antibodies and specific tyrosine kinase inhibitors have proven to be partially efficacious in the treatment of this heterogeneous disease. Induction of an embryonic program of epithelial-to-mesenchymal transition (EMT) in breast cancer, whereupon epithelial tumor cells convert to a more mesenchymal-like phenotype, facilitates the migration, intravasation, and extravasation of tumor cells during metastasis. Breast cancers which exhibit properties of EMT are highly aggressive and resistant to therapy. Activation of ErbB signaling can regulate EMT-associated invasion and migration in normal and malignant mammary epithelial cells, as well as modulating discrete stages of mammary gland development. The purpose of this review is to summarize current information regarding the role of ErbB signaling in aspects of EMT that influence epithelial cell plasticity during mammary gland development and tumorigenesis. How this information may contribute to the improvement of therapeutic approaches in breast cancer will also be addressed.
Topics: Animals; Breast Neoplasms; Cell Dedifferentiation; Cell Differentiation; Cell Transdifferentiation; Embryonic Development; Epidermal Growth Factor; Epithelial Cells; Female; Humans; Ligands; Mammary Glands, Animal; Mammary Glands, Human; Mammary Neoplasms, Experimental; Mesenchymal Stem Cells; Neoplasm Invasiveness; Neoplasm Metastasis; Receptor Protein-Tyrosine Kinases; Signal Transduction
PubMed: 20369376
DOI: 10.1007/s10911-010-9172-2 -
Biomaterials Apr 2019The intricate architecture of branched tissues and organs has fascinated scientists and engineers for centuries. Yet-despite their ubiquity-the biophysical and... (Review)
Review
The intricate architecture of branched tissues and organs has fascinated scientists and engineers for centuries. Yet-despite their ubiquity-the biophysical and biochemical mechanisms by which tissues and organs undergo branching morphogenesis remain unclear. With the advent of three-dimensional (3D) culture models, an increasingly powerful and diverse set of tools are available for investigating the development and remodeling of branched tissues and organs. In this review, we discuss the application of 3D culture models for studying branching morphogenesis of the mammary gland and the mammalian lung in the context of normal development and disease. While current 3D culture models lack the cellular and molecular complexity observed in vivo, we emphasize how these models can be used to answer targeted questions about branching morphogenesis. We highlight the specific advantages and limitations of using 3D culture models to study the dynamics and mechanisms of branching in the mammary gland and mammalian lung. Finally, we discuss potential directions for future research and propose strategies for engineering the next generation of 3D culture models for studying tissue morphogenesis.
Topics: Animals; Equipment Design; Humans; Lab-On-A-Chip Devices; Lung; Mammary Glands, Human; Morphogenesis; Organ Culture Techniques; Organoids; Tissue Engineering
PubMed: 30174198
DOI: 10.1016/j.biomaterials.2018.08.043 -
Journal of Mammary Gland Biology and... Jun 2013TBX2 and TBX3, closely related members of the T-box family of transcription factor genes, are expressed in mammary tissue in both humans and mice. Ulnar mammary syndrome... (Review)
Review
TBX2 and TBX3, closely related members of the T-box family of transcription factor genes, are expressed in mammary tissue in both humans and mice. Ulnar mammary syndrome (UMS), an autosomal dominant disorder caused by mutations in TBX3, underscores the importance of TBX3 in human breast development, while abnormal mammary gland development in Tbx2 or Tbx3 mutant mice provides models for experimental investigation. In addition to their roles in mammary development, aberrant expression of TBX2 and TBX3 is associated with breast cancer. TBX2 is preferentially amplified in BRCA1/2-associated breast cancers and TBX3 overexpression has been associated with advanced stage disease and estrogen-receptor-positive breast tumors. The regulation of Tbx2 and Tbx3 and the downstream targets of these genes in development and disease are not as yet fully elucidated. However, it is clear that the two genes play unique, context-dependent roles both in mammary gland development and in mammary tumorigenesis.
Topics: Animals; Breast Neoplasms; Female; Gene Expression Regulation, Developmental; Humans; Mammary Glands, Animal; Mammary Glands, Human; T-Box Domain Proteins
PubMed: 23624936
DOI: 10.1007/s10911-013-9282-8 -
Journal of Mammary Gland Biology and... Jun 2011Breast cancer is a heterogeneous disease comprised of at least five major tumor subtypes that coalesce as the second leading cause of cancer death in women in the United... (Review)
Review
Breast cancer is a heterogeneous disease comprised of at least five major tumor subtypes that coalesce as the second leading cause of cancer death in women in the United States. Although metastasis clearly represents the most lethal characteristic of breast cancer, our understanding of the molecular mechanisms that govern this event remains inadequate. Clinically, ~30% of breast cancer patients diagnosed with early-stage disease undergo metastatic progression, an event that (a) severely limits treatment options, (b) typically results in chemoresistance and low response rates, and (c) greatly contributes to aggressive relapses and dismal survival rates. Transforming growth factor-β (TGF-β) is a pleiotropic cytokine that regulates all phases of postnatal mammary gland development, including branching morphogenesis, lactation, and involution. TGF-β also plays a prominent role in suppressing mammary tumorigenesis by preventing mammary epithelial cell (MEC) proliferation, or by inducing MEC apoptosis. Genetic and epigenetic events that transpire during mammary tumorigenesis conspire to circumvent the tumor suppressing activities of TGF-β, thereby permitting late-stage breast cancer cells to acquire invasive and metastatic phenotypes in response to TGF-β. Metastatic progression stimulated by TGF-β also relies on its ability to induce epithelial-mesenchymal transition (EMT) and the expansion of chemoresistant breast cancer stem cells. Precisely how this metamorphosis in TGF-β function comes about remains incompletely understood; however, recent findings indicate that the initiation of oncogenic TGF-β activity is contingent upon imbalances between its canonical and noncanonical signaling systems. Here we review the molecular and cellular contributions of noncanonical TGF-β effectors to mammary tumorigenesis and metastatic progression.
Topics: Animals; Breast Neoplasms; Cell Transformation, Neoplastic; Disease Progression; Epithelial-Mesenchymal Transition; Female; Humans; Mammary Glands, Animal; Mammary Glands, Human; Mammary Neoplasms, Experimental; Signal Transduction; Transforming Growth Factor beta
PubMed: 21448580
DOI: 10.1007/s10911-011-9207-3 -
The International Journal of... 2011Exosomes are 40-100 nm intraluminal vesicles that are released by cells upon fusion of multivesicular endosomes (MVEs) with the plasma membrane. The Rab family of small... (Review)
Review
Exosomes are 40-100 nm intraluminal vesicles that are released by cells upon fusion of multivesicular endosomes (MVEs) with the plasma membrane. The Rab family of small GTPases, including Rab27A and Rab27B, control different steps of exosome release, including transport of MVEs and docking at the plasma membrane. Exosomes are long range message particles that mediate communication between cells in physiological conditions such as mammary gland development and lactation, but also in pathology such as breast cancer. Metastasis is the culmination of cancer progression and involves a complex interaction with the local and distant environment. Exosome messaging contributes to tumor environment interactions such as immune escape, thrombosis and myofibroblast differentiation, thereby modulating metastatic niche preparation.
Topics: Animals; Breast; Breast Neoplasms; Cell Adhesion; Disease Progression; Drug Resistance, Neoplasm; Endosomal Sorting Complexes Required for Transport; Exosomes; Female; Humans; Hydrogen-Ion Concentration; Lysophospholipids; Mice; Models, Biological; Monoglycerides; Neoplasm Invasiveness; Neovascularization, Pathologic; Pregnancy; Signal Transduction; Stromal Cells; rab GTP-Binding Proteins
PubMed: 22161843
DOI: 10.1387/ijdb.113391ah -
Cells Oct 2021Breast cancers display dynamic reprogrammed metabolic activities as cancers develop from premalignant lesions to primary tumors, and then metastasize. Numerous advances... (Review)
Review
Breast cancers display dynamic reprogrammed metabolic activities as cancers develop from premalignant lesions to primary tumors, and then metastasize. Numerous advances focus on how tumors develop pro-proliferative metabolic signaling that differs them from adjacent, non-transformed epithelial tissues. This leads to targetable oncogene-driven liabilities among breast cancer subtypes. Other advances demonstrate how microenvironments trigger stress-response at single-cell resolution. Microenvironmental heterogeneities give rise to cell regulatory states in cancer cell spheroids in three-dimensional cultures and at stratified terminal end buds during mammary gland morphogenesis, where stress and survival signaling juxtapose. The cell-state specificity in stress signaling networks recapture metabolic evolution during cancer progression. Understanding lineage-specific metabolic phenotypes in experimental models is useful for gaining a deeper understanding of subtype-selective breast cancer metabolism.
Topics: Adaptation, Physiological; Breast Neoplasms; Disease Progression; Female; Humans; Mammary Glands, Human; Morphogenesis; Stress, Physiological
PubMed: 34685621
DOI: 10.3390/cells10102641 -
Cell Reports Jan 2024Extensive remodeling of the female mammary epithelium during development and pregnancy has been linked to cancer susceptibility. The faithful response of mammary...
Extensive remodeling of the female mammary epithelium during development and pregnancy has been linked to cancer susceptibility. The faithful response of mammary epithelial cells (MECs) to hormone signaling is key to avoiding breast cancer development. Here, we show that lactogenic differentiation of murine MECs requires silencing of genes encoding ribosomal RNA (rRNA) by the antisense transcript PAPAS. Accordingly, knockdown of PAPAS derepresses rRNA genes, attenuates the response to lactogenic hormones, and induces malignant transformation. Restoring PAPAS levels in breast cancer cells reduces tumorigenicity and lung invasion and activates many interferon-regulated genes previously linked to metastasis suppression. Mechanistically, PAPAS transcription depends on R-loop formation at the 3' end of rRNA genes, which is repressed by RNase H1 and replication protein A (RPA) overexpression in breast cancer cells. Depletion of PAPAS and upregulation of RNase H1 and RPA in human breast cancer underpin the clinical relevance of our findings.
Topics: Pregnancy; Female; Mice; Animals; Humans; Mammary Glands, Animal; Breast; Cell Differentiation; Breast Neoplasms; Cell Transformation, Neoplastic; Epithelial Cells
PubMed: 38180837
DOI: 10.1016/j.celrep.2023.113644 -
Journal of Mammary Gland Biology and... Mar 2010Most of the development and functional differentiation in the mammary gland occur after birth. Epigenetics is defined as the stable alterations in gene expression... (Review)
Review
Most of the development and functional differentiation in the mammary gland occur after birth. Epigenetics is defined as the stable alterations in gene expression potential that arise during development and proliferation. Epigenetic changes are mediated at the biochemical level by the chromatin conformation initiated by DNA methylation, histone variants, post-translational modifications of histones, non-histone chromatin proteins, and non-coding RNAs. Epigenetics plays a key role in development. However, very little is known about its role in the developing mammary gland or how it might integrate the many signalling pathways involved in mammary gland development and function that have been discovered during the past few decades. An inverse relationship between marks of closed (DNA methylation) or open chromatin (DnaseI hypersensitivity, certain histone modifications) and milk protein gene expression has been documented. Recent studies have shown that during development and functional differentiation, both global and local chromatin changes occur. Locally, chromatin at distal regulatory elements and promoters of milk protein genes gains a more open conformation. Furthermore, changes occur both in looping between regulatory elements and attachment to nuclear matrix. These changes are induced by developmental signals and environmental conditions. Additionally, distinct epigenetic patterns have been identified in mammary gland stem and progenitor cell sub-populations. Together, these findings suggest that epigenetics plays a role in mammary development and function. With the new tools for epigenomics developed in recent years, we now can begin to establish a framework for the role of epigenetics in mammary gland development and disease.
Topics: Animals; Breast Neoplasms; Cell Differentiation; Chromatin; Chromatin Assembly and Disassembly; Epigenesis, Genetic; Female; Gene Expression Regulation, Neoplastic; Histones; Humans; Mammary Glands, Animal; Mammary Glands, Human; RNA, Untranslated; Stem Cells; Transcription Factors; Transcription, Genetic
PubMed: 20157770
DOI: 10.1007/s10911-010-9170-4 -
Advances in Nutrition (Bethesda, Md.) May 2015Breastfeeding has been regarded first and foremost as a means of nutrition for infants, providing essential components for their unique growth and developmental... (Review)
Review
Breastfeeding has been regarded first and foremost as a means of nutrition for infants, providing essential components for their unique growth and developmental requirements. However, breast milk is also rich in immunologic factors, highlighting its importance as a mediator of protection. In accordance with its evolutionary origin, the mammary gland offers via the breastfeeding route continuation of the maternal to infant immunologic support established in utero. At birth, the infant's immune system is immature, and although it was exposed to the maternal microbial flora during pregnancy, it experiences an abrupt change in its microbial environment during and after birth, which is challenging and renders the infant highly susceptible to infection. Active and passive immunity protects the infant via breast milk, which is rich in immunoglobulins, lactoferrin, lysozyme, cytokines, and numerous other immunologic factors, including maternal leukocytes. Breast milk leukocytes provide active immunity and promote development of immunocompetence in the infant. Additionally, it has been speculated that they play a role in the protection of the mammary gland from infection. Leukocytes are thought to exert these functions via phagocytosis, secretion of antimicrobial factors and/or antigen presentation in both the mammary gland and the gastrointestinal tract of the infant, and also in other infant tissues, where they are transported via the systemic circulation. Recently, it has been demonstrated that breast milk leukocytes respond dynamically to maternal as well as infant infections, and are fewer in nonexclusively compared with exclusively breastfeeding dyads, further emphasizing their importance for both the mother and infant. This review summarizes the current knowledge of human milk leukocytes and factors influencing them, and presents recent novel findings supporting their potential as a diagnostic marker for infections of the lactating breast and of the breastfed infant.
Topics: Animals; Breast Diseases; Breast Feeding; Humans; Immune System; Infant; Infections; Lactation; Leukocytes; Mammary Glands, Human; Milk, Human; Mothers
PubMed: 25979492
DOI: 10.3945/an.114.007377