title: Developmental signaling pathways regulating mammary stem cells and contributing to the etiology of triple-negative breast cancer.
abstract: Cancer has been considered as temporal and spatial aberrations of normal development in tissues. Similarities between mammary embryonic development and cell transformation suggest that the underlying processes required for mammary gland development are also those perturbed during various stages of mammary tumorigenesis and breast cancer (BC) development. The master regulators of embryonic development Cripto-1, Notch/CSL, and Wnt/β-catenin play key roles in modulating mammary gland morphogenesis and cell fate specification in the embryo through fetal mammary stem cells (fMaSC) and in the adult organism particularly within the adult mammary stem cells (aMaSC), which determine mammary progenitor cell lineages that generate the basal/myoepithelial and luminal compartments of the adult mammary gland. Together with recognized transcription factors and embryonic stem cell markers, these embryonic regulatory molecules can be inappropriately augmented during tumorigenesis to support the tumor-initiating cell (TIC)/cancer stem cell (CSC) compartment, and the effects of their deregulation may contribute for the etiology of BC, in particular the most aggressive subtype of BC, triple-negative breast cancer (TNBC). This in depth review will present evidence of the involvement of Cripto-1, Notch/CSL, and Wnt/β-catenin in the normal mammary gland morphogenesis and tumorigenesis, from fMaSC/aMaSC regulation to TIC generation and maintenance in TNBC. Specific therapies for treating TNBC by targeting these embryonic pathways in TICs will be further discussed, providing new opportunities to destroy not only the bulk tumor, but also TICs that initiate and promote the metastatic spread and recurrence of this aggressive subtype of BC.
authors.affiliation: Tumor Growth Factor Section, Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Building 560, Room 32-40B, 1050 Boyles Street, Ft. Detrick, Frederick, MD, 21702, USA.
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Rangel
authors.affiliation: Tumor Growth Factor Section, Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Building 560, Room 32-40B, 1050 Boyles Street, Ft. Detrick, Frederick, MD, 21702, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Bertolette
authors.affiliation: Tumor Growth Factor Section, Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Building 560, Room 32-40B, 1050 Boyles Street, Ft. Detrick, Frederick, MD, 21702, USA.
authors.forename: Nadia P
authors.initials: NP
authors.lastname: Castro
authors.affiliation: Tumor Growth Factor Section, Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Building 560, Room 32-40B, 1050 Boyles Street, Ft. Detrick, Frederick, MD, 21702, USA.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Klauzinska
authors.affiliation: Tumor Growth Factor Section, Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Building 560, Room 32-40B, 1050 Boyles Street, Ft. Detrick, Frederick, MD, 21702, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Cuttitta
authors.affiliation: Tumor Growth Factor Section, Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Building 560, Room 32-40B, 1050 Boyles Street, Ft. Detrick, Frederick, MD, 21702, USA. salomond@mail.nih.gov.
authors.forename: David S
authors.initials: DS
authors.lastname: Salomon
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D042361:Mammary Glands, Human / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D014157:Transcription Factors
keywords: Cripto-1; Notch/CSL; TIC/CSC; TNBC; Wnt/β-catenin; fMaSC/aMaSC