Molecular Signaling of Progesterone, Growth Hormone, Wnt, and HER in Mammary Glands of Dogs, Rodents, and Humans: New Treatment Target Identification

Abstract

Mammary tumors are the most common form of neoplasia in the bitch. Female dogs are protected when they are spayed before the first estrus cycle, but this effect readily disappears and is already absent when dogs are spayed after the second heat. As the ovaries are removed during spaying, ovarian steroids are assumed to play an essential role in tumor development. The sensitivity toward tumor development is already present during early life, which may be caused by early mutations in stem cells during the first estrus cycles. Later on in life, tumors arise that are mostly steroid-receptor positive, although a small subset of tumors overexpressing human epidermal growth factor 2 (HER2) and some lacking estrogen receptor, progesterone receptor (PR), and HER2 (triple negative) are present, as is the situation in humans. Progesterone (P4), acting through PR, is the major steroid involved in outgrowth of mammary tissue. PRs are expressed in two forms, the progesterone receptor A (PRA) and progesterone receptor B (PRB) isoforms derived from splice variants from a single gene. The dog and the whole family of canids have only a functional PRA isoform, whereas the PRB isoform, if expressed at all, is devoid of intrinsic biological activity. In human breast cancer, overexpression of the PRA isoform is related to more aggressive carcinomas making the dog a unique model to study PRA-related mammary cancer. Administration of P4 to adult dogs results in local mammary expression of growth hormone (GH) and wing less-type mouse mammary tumor virus integration site family 4 (Wnt4). Both proteins play a role in activation of mammary stem cells. In this review, we summarize what is known on P4, GH, and Wnt signaling in canine mammary cancer, how the family of HER receptors could interact with this signaling, and what this means for comparative and translational oncological aspects of human breast cancer development.

Icariin Ameliorate Thiram-Induced Tibial Dyschondroplasia via Regulation of WNT4 and VEGF Expression in Broiler Chickens

“…Therefore, our study adopts the methods of molecular biology affecting VEGF and wingless-type member 4 (WNT4) genes associated with bone calcium absorption. The WNT4 is key regulator in early embryogenesis; stem cells and WNT signaling are involved in the regulation of numerous processes of cell proliferation, differentiation and morphogenesis in humans and other species ( Timmermans-Sprang et al, 2017 ). The WNT4 is a secreted protein from osteoblasts and it has significant affect to inhibit bone resorption ( Hartmann and Tabin, 2000 ; Algandaby et al, 2017 ).…”

Growth Hormone Receptor Regulation in Cancer and Chronic Diseases

“…Autocrine GH may have an even greater role in cancer development than endocrine GH (55). In mammary tissue GH1 expression has been found to be regulated by progesterone (56)(57)(58). GH belongs to the same family as prolactin (59), and in primates GH binds also to the PRLR, which presumably implicates all PRLR-mediated actions including mammary gland differentiation and lactation.…”

Dasatinib inhibition of cSRC prevents the migration and metastasis of canine mammary cancer cells with enhanced Wnt and HER signalling

“…23 However, the cell lines with high Wnt activity and rounded cell morphology had relatively high E-cadherin expression, 24 excluding the likelihood that loss of E-cadherin caused high canonical Wnt activity 25 and elevated β-catenin levels. [26][27][28] Further analysis by quantitative polymerase chain reaction (qPCR) of selected genes showed that the cell lines with high Wnt signalling overexpressed HER2,3 mRNA with LEF1, heat shock protein 90 (HSP90) and ras-like protein (RAC1), among others, and silenced phosphatase and tensin homologue (PTEN) mRNA expression. 20 The loss of PTEN expression in combination with an increased expression level of HER3, which promotes HER2-driven mammary tumour proliferation, 29 could indicate a highly activated PI3K/mammalian target of rapamycin (mTOR) pathway.…”

“…In general, EMT, which is characterized by alterations in cell shape and loss of attachment to other cells and the extracellular matrix (ECM), is caused by loss of E‐cadherin expression . However, the cell lines with high Wnt activity and rounded cell morphology had relatively high E‐cadherin expression, excluding the likelihood that loss of E‐cadherin caused high canonical Wnt activity and elevated β‐catenin levels …”