Wnt Signaling Pathway in Mammary Gland Development and Carcinogenesis

Abstract

The signaling pathway mediated by Wingless-type (Wnt) proteins is highly conserved in evolution. This pivotal pathway is known to regulate cell fate decisions, cell proliferation, morphology, migration, apoptosis, differentiation and stem cell self-renewal. It currently includes the canonical or Wnt/β-catenin pathway in which Wnt proteins bind to ‘frizzled’ receptors, which leads to downstream activation of gene transcription by β-catenin. Second, the noncanonical or β-catenin-independent pathways are now known to be mediated by three possible mechanisms: (1) the Wnt/Ca²⁺ pathway, (2) the Wnt/G protein signaling pathway, and (3) the Wnt/PCP or planar cell polarity pathway. Wnt signaling is implicated at several stages of mammary gland growth and differentiation, and possibly in the involution of mammary gland following lactation. Recent evidence suggests the role of Wnt signaling in human breast cancer involves elevated levels of nuclear and/or cytoplasmic β-catenin using immunohistochemistry, overexpression or downregulation of specific Wnt proteins, overexpression of CKII and sFRP4, downregulation of WIF-1 and sFRP1, as well as amplification of DVL-1. Further research is required to determine how Wnt signaling is involved in the development of different histological types of breast cancer and whether it promotes the viability of cancer stem cells or not.

Molecular insights on basal-like breast cancer

“…This study reported cytoplasmic and nuclear accumulation of -catenin in BLBC, and suggested that β-catenin could be a valuable therapeutic target for this subtype [24]. Nevertheless there is strong evidence of stabilization of β-catenin protein in a majority of human breast tumors, and mouse model systems clearly demonstrate that activated Wnt signaling can promote mammary tumorigenesis [25].…”

FZD7 has a critical role in cell proliferation in triple negative breast cancer

“…Basal-like breast cancer is categorized as TNBC because almost all basal-like breast cancers lack hormone receptor expression and HER2 overexpression (Perou et al, 2000;Sotiriou et al, 2003). Although aberrant activation of Wnt signaling has been observed in breast cancer (Brown, 2001;Turashvili et al, 2006), the correlation of Wnt signaling with TNBC has rarely been investigated. However, canonical Wnt pathway activation in basal-like tumors has been observed (DiMeo et al, 2009;Lindvall et al, 2009).…”

Mammary-digital-nail (MDN) syndrome: a novel phenotype maps to human chromosome 22q12.3–13.1

“…In patients IV 25 , III 10 , IV 19 , and IV 20 ( Figure 2) breasts enlarged dramatically, reaching enormous proportion during a 3-month period before and shortly after menarche. 2 Of note, female patient III 9 , who died at the age of 3 years, well before her premenarche time, presented with ODP only.…”

“…10 Two physicians conducted complete physical examinations and detailed interviews of the medical and family history of the 41 members of the kindred who agreed to participate in the study. Patients III 19 , IV 20 , IV 25 , and IV 28 ( Figure 2) underwent X-rays of hands, feet, and long bones.…”

“…We compared cDNA isolated from skin and/or mammary tissues of four affected family members (two males and two females), IV 19 , IV 25 , IV 21 , and IV 28 ( Figure 2) to that of five unrelated unaffected individuals (three males and two females). Breast tissue was removed solely from females.…”