The covert symphony: cellular and molecular accomplices in breast cancer metastasis.

Breast cancer has emerged as the most commonly diagnosed cancer and primary cause of cancer-related deaths among women worldwide. Although significant progress has been made in targeting the primary tumor, the effectiveness of systemic treatments to prevent metastasis remains limited. Metastatic disease continues to be the predominant factor leading to fatality in the majority of breast cancer patients.

Taking shape: Intercalation within the mammary terminal end bud.

In this issue of Developmental Cell, Pfannenstein and Macara leverage the experimental versatility of the mammary gland to show that intercalation within the terminal end bud is regulated by the tight junction organizing protein ZO-1 and dynamic actin cytoskeletal rearrangements to propel ductal elongation.

Unlocking the secrets of cancer stem cells: Immune checkpoint inhibitors face their formidable foes.

In this issue of Cell Stem Cell, Beziaud et al. show that immunotherapy induces stem-like properties in models of breast cancer. Strikingly, T-cell-derived IFNγ promotes cancer stem cell (CSC) phenotypes, therapy resistance, and metastasis.

Noncanonical Wnt/Ror2 signaling regulates cell-matrix adhesion to prompt directional tumor cell invasion in breast cancer.

Cell-extracellular matrix (ECM) interactions represent fundamental exchanges during tumor progression, yet how particular signal-transduction factors prompt the conversion of tumor cells into migratory populations capable of systemic spread during metastasis remains elusive. We demonstrate that the noncanonical Wnt receptor, Ror2, regulates tumor cell-driven matrix remodeling and invasion in breast cancer. Ror2 loss-of-function (LOF) triggers the disruption of E-cadherin within tumor cells, accompanied by an increase in tumor cell invasion and collagen realignment in three-dimensional cultures.

Laboratory Models for Investigating Breast Cancer Therapy Resistance and Metastasis.

While numerous therapies are highly efficacious in early-stage breast cancers and in particular subsets of breast cancers, therapeutic resistance and metastasis unfortunately arise in many patients. In many cases, tumors that are resistant to standard of care therapies, as well as tumors that have metastasized, are treatable but incurable with existing clinical strategies. Both therapy resistance and metastasis are multi-step processes during which tumor cells must overcome diverse environmental and selective hurdles.

FGFR1-Activated Translation of WNT Pathway Components with Structured 5' UTRs Is Vulnerable to Inhibition of EIF4A-Dependent Translation Initiation.

Cooperativity between WNT and FGF signaling is well documented in embryonic development and cancer progression, but the molecular mechanisms underlying this cross-talk remain elusive. In this study, we interrogated the dynamics of RNA levels, ribosome occupancy, and protein expression as a function of inducible FGF signaling in mouse mammary glands with constitutive WNT hyperactivation. Multiomics correlation analysis revealed a substantial discrepancy between RNA and ribosome occupancy levels versus protein levels.

WNT-Mediated Regulation of FOXO1 Constitutes a Critical Axis Maintaining Pubertal Mammary Stem Cell Homeostasis.

Puberty is characterized by dynamic tissue remodeling in the mammary gland involving ductal elongation, resolution into the mature epithelial bilayer, and lumen formation. To decipher the cellular mechanisms underlying these processes, we studied the fate of putative stem cells, termed cap cells, present in terminal end buds of pubertal mice. Employing a p63-based lineage-tracing strategy, we identified a unipotent fate for proliferative cap cells that only generated cells with basal features.

The mammary stem cell hierarchy: a looking glass into heterogeneous breast cancer landscapes.

The mammary gland is a dynamic organ that undergoes extensive morphogenesis during the different stages of embryonic development, puberty, estrus, pregnancy, lactation and involution. Systemic and local cues underlie this constant tissue remodeling and act by eliciting an intricate pattern of responses in the mammary epithelial and stromal cells. Decades of studies utilizing methods such as transplantation and lineage-tracing have identified a complex hierarchy of mammary stem cells, progenitors and differentiated epithelial cells that fuel mammary epithelial development.

Ror2 regulates branching, differentiation, and actin-cytoskeletal dynamics within the mammary epithelium.

Wnt signaling encompasses β-catenin-dependent and -independent networks. How receptor context provides Wnt specificity in vivo to assimilate multiple concurrent Wnt inputs throughout development remains unclear. Here, we identified a refined expression pattern of Wnt/receptor combinations associated with the Wnt/β-catenin-independent pathway in mammary epithelial subpopulations.

STAT3 signaling is activated preferentially in tumor-initiating cells in claudin-low models of human breast cancer.

In breast cancer, a subset of tumor-initiating cells (TIC) or "cancer stem cells" are thought to be responsible for tumor maintenance, treatment resistance, and disease recurrence. While current breast cancer stem cell markers (e.g.

Paracrine signaling in mammary gland development: what can we learn about intratumoral heterogeneity?

Paracrine signaling mechanisms play a critical role in both normal mammary gland development and breast cancer. Dissection of these mechanisms using genetically engineered mouse models has provided significant insight into our understanding of the mechanisms that guide intratumoral heterogeneity. In the following perspective, we briefly review some of the emerging concepts in this field and emphasize why elucidation of these pathways will be important for future progress in devising new and improved combinatorial therapeutic approaches for breast and other solid cancers.

Pygopus 2: tilting the Wnt-Notch balance in mammary epithelial lineage determination.

The mammary gland requires the coordinated efforts of multiple epithelial cell lineages to build an organized bilayered ductal network. How epigenetic regulators direct decisions of cell-fate and lineage determination in cooperation with intrinsic transcriptional factors and extrinsic signaling factors remains a fundamental question in the field of developmental biology. Recent work sheds new light on the role of the histone methylation reader Pygopus 2 in coordinating the balance of self-renewal Wnt signals with luminal-specific Notch signals in mammary epithelial lineage determination.

Fibroblast growth factor receptor signaling is essential for normal mammary gland development and stem cell function.

Fibroblast growth factor (FGF) signaling plays an important role in embryonic stem cells and adult tissue homeostasis, but the function of FGFs in mammary gland stem cells is less well defined. Both FGFR1 and FGFR2 are expressed in basal and luminal mammary epithelial cells (MECs), suggesting that together they might play a role in mammary gland development and stem cell dynamics. Previous studies have demonstrated that the deletion of FGFR2 resulted only in transient developmental defects in branching morphogenesis.

Pregnancy-induced noncoding RNA (PINC) associates with polycomb repressive complex 2 and regulates mammary epithelial differentiation.

Pregnancy-induced noncoding RNA (PINC) and retinoblastoma-associated protein 46 (RbAp46) are upregulated in alveolar cells of the mammary gland during pregnancy and persist in alveolar cells that remain in the regressed lobules following involution. The cells that survive involution are thought to function as alveolar progenitor cells that rapidly differentiate into milk-producing cells in subsequent pregnancies, but it is unknown whether PINC and RbAp46 are involved in maintaining this progenitor population. Here, we show that, in the post-pubertal mouse mammary gland, mPINC is enriched in luminal and alveolar progenitors.

The pINDUCER lentiviral toolkit for inducible RNA interference in vitro and in vivo.

The discovery of RNAi has revolutionized loss-of-function genetic studies in mammalian systems. However, significant challenges still remain to fully exploit RNAi for mammalian genetics. For instance, genetic screens and in vivo studies could be broadly improved by methods that allow inducible and uniform gene expression control.

Wnt and mammary stem cells: hormones cannot fly wingless.

The mammary stem cell and its local microenvironment are central for the maintenance of proper tissue homeostasis during normal development. Defining the hierarchical organization of the epithelial subtypes in the mammary gland and the molecular pathways guiding their development has begun to provide a framework for understanding how cancer stem cells sustain the progression and heterogeneity of breast cancers. The Wnt pathway plays a fundamental role in multiple adult stem cells, as well as in orchestrating proper mammary gland development and maintenance.

TGF-beta promotes Th17 cell development through inhibition of SOCS3.

TGF-beta, together with IL-6 and IL-21, promotes Th17 cell development. IL-6 and IL-21 induce activation of STAT3, which is crucial for Th17 cell differentiation, as well as the expression of suppressor of cytokine signaling (SOCS)3, a major negative feedback regulator of STAT3-activating cytokines that negatively regulates Th17 cells. However, it is still largely unclear how TGF-beta regulates Th17 cell development and which TGF-beta signaling pathway is involved in Th17 cell development.

Loss of TGF-beta or Wnt5a results in an increase in Wnt/beta-catenin activity and redirects mammary tumour phenotype.

Introduction: The tumour-suppressive effects of transforming growth factor-beta (TGF-beta) are well documented; however, the mechanistic basis of these effects is not fully understood. Previously, we showed that a non-canonical member of the Wingless-related protein family, Wnt5a, is required for TGF-beta-mediated effects on mammary development. Several lines of evidence support the hypothesis that Wnt5a acts as a tumour suppressor.

Loss of protein inhibitors of activated STAT-3 expression in glioblastoma multiforme tumors: implications for STAT-3 activation and gene expression.

Purpose: STATs activate transcription in response to numerous cytokines, controlling proliferation, gene expression, and apoptosis. Aberrant activation of STAT proteins, particularly STAT-3, is implicated in the pathogenesis of many cancers, including GBM, by promoting cell cycle progression, stimulating angiogenesis, and impairing tumor immune surveillance. Little is known about the endogenous STAT inhibitors, the PIAS proteins, in human malignancies.

Role for primary cilia in the regulation of mouse ovarian function.

Ift88 is a component of the intraflagellar transport complex required for formation and maintenance of cilia. Disruption of Ift88 results in depletion of cilia. The goal of the current study was to determine the role of primary cilia in ovarian function.

Wnt5a is required for proper mammary gland development and TGF-beta-mediated inhibition of ductal growth.

Transforming growth factor-beta (TGF-beta) plays an essential role in growth and patterning of the mammary gland, and alterations in its signaling have been shown to illicit biphasic effects on tumor progression and metastasis. We demonstrate in mice that TGF-beta (Tgfbeta) regulates the expression of a non-canonical signaling member of the wingless-related protein family, Wnt5a. Loss of Wnt5a expression has been associated with poor prognosis in breast cancer patients; however, data are lacking with regard to a functional role for Wnt5a in mammary gland development.