The Potential Role of Hedgehog Signaling in the Luminal/Basal Phenotype of Breast Epithelia and in Breast Cancer Invasion and Metastasis

Abstract

The epithelium of the lactiferous ducts in the breast is comprised of luminal epithelial cells and underlying basal myoepithelial cells. The regulation of cell fate and transit of cells between these two cell types remains poorly understood. This relationship becomes of greater importance when studying the subtypes of epithelial breast carcinoma, which are categorized according to their expression of luminal or basal markers. The epithelial mesenchymal transition (EMT) is a pivotal event in tumor invasion. It is important to understand mechanisms that regulate this process, which bears relation to the normal dynamic of epithelial/basal phenotype regulation in the mammary gland. Understanding this process could provide answers for the regulation of EMT in breast cancer, and thereby identify potential targets for therapy. Evidence points towards a role for hedgehog signaling in breast tissue homeostasis and also in mammary neoplasia. This review examines our current understanding of role of the hedgehog-signaling (Hh) pathway in breast epithelial cells both during breast development and homeostasis and to assess the potential misappropriation of Hh signals in breast neoplasia, cancer stem cells and tumor metastasis via EMT.

Keywords: basal-like breast cancer; breast cancer; epithelial mesenchymal transition; hedgehog signaling; luminal breast cancer; metastasis.

Figure 1

The prenatal stages of mammary gland tissue development. The mammary gland forms as early as day 10 of gestation in mice by the formation of the milk line. This is followed by at least four stages of development. At the time of birth the breast tissue is composed of three distinct layers including the mammary epithelium, mammary mesenchyme. (Which forms the structure of the secondary sprouts), and the dermis. Above are the expression patterns of active signaling and necessary for prenatal mammary gland formation. Illustrated in the top are the hedgehog components associated with those stages of development in mouse embryonic study.

Figure 2

Postnatal mammary gland development is composed of several stages (after birth, puberty, adult, pregnancy, lactation, involution, and menopause). Highlighted are the known key hedgehog signaling components expression found essential at each stage of mammary adult female breast. It should be noted that other Hh components are found expressed at various stages, yet the highlighted compounds are the ones found important for that stage of development.

Figure 3

The mammary gland stem cell types and the corresponding breast cancer type. (a) The expansion of breast cell types from a single progenitor; (b) The molecular sub classification of breast cancers, their hypothesized origin, and percentage prevalence at clinical presentation; (c) The involvement of EMT process in breast cancer and a suggested level of EMT according to the sub classification of breast cancer; (d) The associated prognosis of various breast cancer subtypes.

Figure 4

The Hedgehog signaling pathway. (A) The canonical hedgehog signaling components, the secreted ligands (Sonic Hedgehog (Shh), Indian Hedgehog (Ihh), and Desert Hedgehog (Dhh)) and the Patched family hedgehog receptors Patched-1 (Ptch-1) and Patched-2 (Ptch-2). Both patched receptors antagonize the function of the Smoothened (Smo) transmembrane effector protein in the absence of the ligand, therefore inhibiting the expression of one or more of the Gli (Glioma-associated oncogene homologue) family of transcription factors (Gli-2 or Gli-3) [1,4,5,18]. In the absence of ligand, Gli is sequestered in the cytoplasm by binding to form a large complex protein with the Kinesin-like Costal2 and the serine-threonine kinase Fused [1,2,4,15,18]; (B) Hedgehog signaling can be activated through three known non-canonical pathways, including Shh-mediated ERK activation in mammary epithelial cells, Wnt signaling pathway involvement in the expression and function of Gli proteins, and the atypical interaction of core Hh pathway components with each other [15,16,17].

Figure 4

The Hedgehog signaling pathway. (A) The canonical hedgehog signaling components, the secreted ligands (Sonic Hedgehog (Shh), Indian Hedgehog (Ihh), and Desert Hedgehog (Dhh)) and the Patched family hedgehog receptors Patched-1 (Ptch-1) and Patched-2 (Ptch-2). Both patched receptors antagonize the function of the Smoothened (Smo) transmembrane effector protein in the absence of the ligand, therefore inhibiting the expression of one or more of the Gli (Glioma-associated oncogene homologue) family of transcription factors (Gli-2 or Gli-3) [1,4,5,18]. In the absence of ligand, Gli is sequestered in the cytoplasm by binding to form a large complex protein with the Kinesin-like Costal2 and the serine-threonine kinase Fused [1,2,4,15,18]; (B) Hedgehog signaling can be activated through three known non-canonical pathways, including Shh-mediated ERK activation in mammary epithelial cells, Wnt signaling pathway involvement in the expression and function of Gli proteins, and the atypical interaction of core Hh pathway components with each other [15,16,17].