Osteoinductive squamous cell carcinoma associated with a putative novel papillomavirus on the digit of a cat.

CASE HISTORY AND CLINICAL FINDINGS: An approximately 10-year-old, castrated male domestic short-haired cat developed swelling and ulceration of the second digit of the right front paw. Radiographs revealed a spherical soft tissue swelling with irregular distal margins that contained multiple lacy mineral opacities. The digit was amputated and submitted for histology. No recurrence has been observed 7 months after amputation. PATHOLOGICAL AND MOLECULAR FINDINGS: Histology revealed a moderately well-circumscribed proliferation of well-differentiated squamous cells arranged in trabeculae and nests. Numerous thin spicules of osseous metaplasia were visible throughout the neoplasm. Around 70% of the neoplastic cells contained papillomavirus-induced cell changes including large amphophilic cytoplasmic bodies and cells with shrunken nuclei surrounded by a clear halo. Intense p16CDKN2A protein immunostaining was visible within the neoplastic cells, suggesting papillomavirus-induced changes in cell regulation. A DNA sequence from a putative novel Taupapillomavirus type was amplified from the neoplasm. DIAGNOSIS: Osteoinductive squamous cell carcinoma associated with a putative novel papillomavirus type. CLINICAL RELEVANCE: The findings in this case increase the number of papillomavirus types known to infect cats, and the squamous cell carcinoma had histological features that have not been previously reported. The neoplasm was not as invasive as is typical for a squamous cell carcinoma and excision appeared curative. This is the first report of an osteoinductive squamous cell carcinoma of the skin of cats and the neoplasm had a unique radiographic appearance.

Temporally regulated overexpression of parathyroid hormone-related protein in the mammary gland reveals distinct fetal and pubertal phenotypes.

We have previously demonstrated that overexpression of parathyroid hormone-related protein (PTHrP) in the mammary glands of transgenic mice results in defects in ductal elongation and branching during puberty and in lobuloalveolar development during pregnancy. In addition, we have shown that PTHrP is necessary for the formation of the initial ductal tree during embryonic mammary development. In order to examine the effect of varying the timing of PTHrP overexpression on mammary development, we created tetracycline-regulated, K14-tTA/Tet(O)-PTHrP double transgenic mice. In this report, we document that this 'tet-off' system directs transgene expression to the mammary gland and that it is fully repressed in the presence of tetracycline. Using these mice, we demonstrate that transient overexpression of PTHrP before birth causes defects in ductal branching during puberty and that overexpression of PTHrP during puberty decreases the rate of ductal elongation. Furthermore, we demonstrate that if PTHrP overexpression is initiated after ductal morphogenesis is completed, lobuloalveolar development is unaffected. Finally, we demonstrate that the impairment in ductal elongation caused by PTHrP is associated with an increase in the basal rate of epithelial cell apoptosis in terminal end buds and a failure to increase end bud cell proliferation and decrease apoptosis in response to estrogen and progesterone.

Mammary ductal and alveolar development: lesson learned from genetically manipulated mice.

The mammary gland has been an area of great interest to developmental biologists for many years because its formation involves many fundamental processes that are central to the development of other organs. Although mammary development has been well described structurally, the molecules and signaling mechanisms that are involved are still largely undefined. For the last several years, intensive effort has been made to understand the molecular mechanisms involved in mammary development. With the recent advances in transgenic and knockout technologies, the ability to delete and/or alter the expression of certain genes in the mouse genome has allowed us to begin to elucidate the mechanisms underlying mammary gland development. In this review, we discuss several mouse models that have provided insight into the molecules and signaling mechanisms that govern ductal development and lobuoloalveolar differentiation in the mammary gland.

Parathyroid hormone-related protein signaling is necessary for sexual dimorphism during embryonic mammary development.

Male mice lack mammary glands due to the interaction of circulating androgens with local epithelial-mesenchymal signaling in the developing mammary bud. Mammary epithelial cells induce androgen receptor (AR) within the mammary mesenchyme and, in response to androgens, the mesenchyme condenses around the epithelial bud, destroying it. We show that this process involves apoptosis and that, in the absence of parathyroid hormone-related protein (PTHrP) or its receptor, the PTH/PTHrP receptor (PPR1), it fails due to a lack of mesenchymal AR expression. In addition, the expression of tenascin C, another marker of the mammary mesenchyme, is also dependent on PTHrP. PTHrP expression is initiated on E11 and, within the ventral epidermis, is restricted to the forming mammary epithelial bud. In contrast, PPR1 expression is not limited to the mammary bud, but is found generally within the subepidermal mesenchyme. Finally, transgenic overexpression of PTHrP within the basal epidermis induces AR and tenasin C expression within the ventral dermis, suggesting that ectopic expression of PTHrP can induce the ventral mesenchyme to express mammary mesenchyme markers. We propose that PTHrP expression specifically within the developing epithelial bud acts as a dominant signal participating in cell fate decisions leading to a specialized mammary mesenchyme.

Parathyroid hormone-related protein: a developmental regulatory molecule necessary for mammary gland development.

Parathyroid hormone-related protein (PTHrP) was originally identified as the tumor factor responsible for a clinical syndrome known as humoral hypercalcemia of malignancy. It is now appreciated that PTHrP3 is a developmental regulatory molecule expressed during the formation of a wide variety of organs. Recently, our laboratory has demonstrated that PTHrP is necessary for mammary gland development. Our studies have suggested that this molecule participates in the regulation of epithelial-mesenchymal interactions during embryonic mammary development and perhaps also during adolescent ductal morphogenesis. In addition, it has been suggested that PTHrP plays a critical role in the establishment of bone metastases in breast cancer. In this article, we will discuss the current knowledge of the mechanisms underlying PTHrPs actions during normal mammary development and in breast cancer.

Stromal cells are critical targets in the regulation of mammary ductal morphogenesis by parathyroid hormone-related protein.

Parathyroid hormone-related protein (PTHrP) was originally identified as the tumor product responsible for humoral hypercalcemia of malignancy. It is now known that PTHrP is produced by many normal tissues in which it appears to play a role as a developmental regulatory molecule. PTHrP is a normal product of mammary epithelial cells, and recent experiments in our laboratory have demonstrated that overexpression or underexpression of PTHrP in the murine mammary gland leads to severe disruptions in its development. The nature of these phenotypes suggests that PTHrP acts to modulate branching growth during mammary development by regulating mammary stromal cell function. We now demonstrate that throughout mammary development, during periods of active ductal-branching morphogenesis, PTHrP is produced by epithelial cells, whereas the PTH/PTHrP receptor is expressed on stromal cells. In addition, we show that mammary stromal cells in culture contain specific binding sites for amino terminal PTHrP and respond with an increase in intracellular cAMP. Finally, we demonstrate that the mammary mesenchyme must express the PTH/PTHrP receptor in order to support mammary epithelial cell morphogenesis. These results demonstrate that PTHrP and the PTH/PTHrP receptor represent an epithelial/mesenchymal signaling circuit that is necessary for mammary morphogenesis and that stromal cells are a critical target for PTHrP's action in the mammary gland.

Rescue of the parathyroid hormone-related protein knockout mouse demonstrates that parathyroid hormone-related protein is essential for mammary gland development.

Parathyroid hormone-related protein (PTHrP) was originally discovered as a tumor product that causes humoral hypercalcemia of malignancy. PTHrP is now known to be widely expressed in normal tissues and growing evidence suggests that it is an important developmental regulatory molecule. We had previously reported that overexpression of PTHrP in the mammary glands of transgenic mice impaired branching morphogenesis during sexual maturity and early pregnancy. We now demonstrate that PTHrP plays a critical role in the epithelial-mesenchymal communications that guide the initial round of branching morphogenesis that occurs during the embryonic development of the mammary gland. We have rescued the PTHrP-knockout mice from neonatal death by transgenic expression of PTHrP targeted to chondrocytes. These rescued mice are devoid of mammary epithelial ducts. We show that disruption of the PTHrP gene leads to a failure of the initial round of branching growth that is responsible for transforming the mammary bud into the rudimentary mammary duct system. In the absence of PTHrP, the mammary epithelial cells degenerate and disappear. The ability of PTHrP to support embryonic mammary development is a function of amino-terminal PTHrP, acting via the PTH/PTHrP receptor, for ablation of the PTH/PTHrP receptor gene recapitulates the phenotype of PTHrP gene ablation. We have localized PTHrP expression to the embryonic mammary epithelial cells and PTH/PTHrP receptor expression to the mammary mesenchyme using in situ hybridization histochemistry. Finally, we have rescued mammary gland development in PTHrP-null animals by transgenic expression of PTHrP in embryonic mammary epithelial cells. We conclude that PTHrP is a critical epithelial signal received by the mammary mesenchyme and involved in supporting the initiation of branching morphogenesis.

Parathyroid hormone-related protein: from hypercalcemia of malignancy to developmental regulatory molecule.

Parathyroid hormone-related protein (PTHrP) was originally discovered because of its role in humoral hypercalcemia of malignancy (HHM), a common metabolic complication of many types of cancer. In HHM, PTHrP is released into the circulation by malignant cells and cross reacts with parathyroid hormone (PTH) receptors in bone and kidney, which results in hypercalcemia. In recent years, it has become clear that PTHrP is a normal product of many adult and fetal tissues where it appears to act in an autocrine and/or paracrine fashion to regulate organogenesis. This article explores the molecular evolution of PTHrP and how this understanding has begun to shed some light on the molecular mechanisms responsible for the biochemical manifestations of HHM. In addition, the normal biological function of PTHrP is discussed, with an emphasis on its role as a developmental regulatory molecule.