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.
Highlights
Mammary tumors are the most common neoplasms in intact bitches with an estimated life-time risk of 1:4
This review focuses on what is known of P4, growth hormone (GH), and Wnt signaling in canine mammary carcinomas in relation to what is known in other species, especially human breast cancer
We have shown that canine progesterone receptor A (PRA) has an expected hPRA-comparable transcriptional activity, whereas canine progesterone receptor B (PRB) has low to absent transactivation potential
Summary
Mammary tumors are the most common neoplasms in intact bitches with an estimated life-time risk of 1:4. A subset of mammary carcinomas present as simple carcinomas that may be derived from mutated epithelial progenitor cells and are comparable to the most common form of human breast cancer, the ductal carcinomas. More often than in humans, dogs may present with complex carcinomas that contain various differentiation pathways within a single affected mammary gland These tumors may be derived from mutations in the most basic and early form of stem cells. Tumor cells with stem cell properties, such as phenotypical epithelial mesenchymal transition (EMT) and elevated activity of the canonical Wnt pathway, play an important role in regrowth and metastasis [17, 18] In both humans and dogs, most mammary carcinomas are initially hormone dependent [i.e., express receptors for P4 (PR) and E2 (ER)]. The remaining tumors are often categorized as human epidermal growth factor 2 (HER2) positive (overexpressing HER2) or as triple-negative breast cancer (TNBC) (i.e., devoid of PR and ER and no overexpression of HER2) [1, 5, 7,8,9, 19]
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