Most breast cancers that occur in women express estrogen receptor α (ERα). However, a large subset of these cancers either does not initially respond to anti-estrogen therapy or develops resistance ...to such treatment modalities. One postulated mechanism of this failure is signaling cross talk between hormones and local growth factors. To examine these complex interactions in vivo , we assessed the effects of estrogen on transforming growth factor α (TGFα)- and prolactin (PRL)-induced mammary tumorigenesis in transgenic mice. Both PRL and estrogen reduced the latency of TGFα-induced oncogenesis, resulting in tumors that were variably ERα-positive, but were progesterone receptor-negative. However, despite elevated ERα levels in NRL-PRL/TGFα glands, tumor latency was not reduced with increasing estrogen levels, nor increased after ovariectomy. Furthermore, PRL and TGFα in combination blocked the mitogenic effects of estrogen, dramatically reduced progesterone receptor levels, and diminished ERα down-regulation in response to circulating estrogen levels, in contrast to the other genotypes. Notably, however, ductal morphology remained responsive to estrogen, indicating that TGFα and PRL in combination can inhibit some, but not all, estrogenic signals. Both in vitro and in vivo , PRL and TGFα cooperatively enhanced Akt phosphorylation, which is associated with endocrine resistance in human disease. These findings provide insight into the interactions of PRL with growth factors during mammary oncogenesis and suggest combinatorial approaches that may result in improved therapeutic efficacy.
Transgenic models to explore the role of prolactin and its interactions with other factors in mammary oncogenesis have begun to reveal the dynamic contributions of prolactin to the development and ...progression of this disease. Targeting prolactin to mammary epithelial cells mimics the local production of this hormone that is prominent in women, and permits studies in the absence of effects on the ovarian steroid milieu. These models have demonstrated that local production of prolactin is sufficient to induce mammary tumors after a long latency. Prolactin also can potentiate actions of other oncogenic stimuli, decreasing tumor latency and increasing incidence in several models. Augmented proliferation, without alteration of apoptosis, is a consistent feature. Pathways in addition to the well-characterized Jak2-Stat5 pathway, including ERK1/2 and Akt1/2, are implicated in these actions. These studies have also revealed a complex relationship with estrogen; while prolactin increases ERα expression, it does not require estrogenic ligand for lesion development, and indeed, in combination with the EGFR ligand, TGFα, prolactin can contribute to estrogen insensitivity. These studies highlight the utility of these models to decipher the interplay between prolactin and other oncogenic factors in breast cancer, with implications for preventative and therapeutic strategies.
Male breast cancer is rare and has been the focus of limited research. Although the etiology is unclear, conditions increasing circulating prolactin (PRL), as well as estrogen, increase the risk of ...tumorigenesis. We modeled exposure to elevated PRL in transgenic mice, using the mammary-selective, estrogen-insensitive promoter neu-related lipocalin (NRL), to drive PRL expression. Male NRL-PRL mice did not develop mammary tumors. However, in cooperation with the well-characterized oncogene transforming growth factor-α (TGF-α), PRL induced mammary tumors in 100% of male bitransgenic mice. Similar to disease in human males, these tumors expressed variable levels of estrogen receptor-α (ER-α) and androgen receptors. However, carcinogenesis was not responsive to testicular steroids because castration did not alter latency to tumor development or tumor ER-α expression. Interestingly, both NRL-TGF-α/PRL and NRL-PRL males demonstrated increased ductal development, which occurred during puberty, similar to female mice. This outgrowth was diminished in NRL-PRL males treated with ICI 182,780, suggesting that PRL enhances ER-mediated growth. Treatment of MCF-7-derived cells with PRL increased phosphorylation of ER-α at residues implicated in unliganded ER-α activity. Together, these studies suggest that PRL expands the pool of cells susceptible to tumorigenesis, which is then facilitated by PRL and TGF-α cross talk. Activation of ER-α is one mechanism by which PRL may contribute to breast cancer and points to other therapeutic strategies for male patients.
SUMMARY
Mutations in clock genes are associated with abnormal circadian parameters, including sleep. An association has been reported previously between a polymorphism (3111C), situated in the ...3′‐untranslated region (3′‐UTR) of the circadian gene Clock and evening preference. In the present study, this polymorphism was assessed in: (1) 105 control subjects with defined diurnal preference, (2) 26 blind subjects with free‐running circadian rhythms and characterized with regard to circadian period (τ) and (3) 16 delayed sleep phase syndrome patients. The control group was chosen from a larger population (n = 484) by Horne‐Östberg questionnaire analysis, from which three subgroups were selected (evening, intermediate and morning preference). Data from sleep diaries completed by 90% of these subjects showed a strong correlation between preferred and estimated timings of sleep and wake. The mean timings of activities for the evening group were at least 2 h later than the morning group. Genetic analysis showed that, in contrast with the previously published finding, there was no association between 3111C and eveningness. Neither was there an association between 3111C and τ, nor a significant difference in 3111C frequency between the normal and delayed sleep phase syndrome groups. To assess the effect of this polymorphism on messenger RNA (mRNA) translatability, luciferase reporter gene constructs containing the two Clock polymorphic variants in their 3′‐UTR were transfected into COS‐1 cells and luciferase activity measured. No significant difference was observed between the two variants. These results do not support Clock 3111C as a marker for diurnal preference, τ, or delayed sleep phase syndrome in humans.
Prolactin influences mammary development and carcinogenesis through endocrine and autocrine/paracrine mechanisms. In virgin female mice, pro-lactin overexpression under control of a mammary selective ...nonhormonally responsive promoter, neu-related lipocalin, results in estrogen receptor α (ERα)-positive and ERα-negative adenocarcinomas. However, disease
in vivo occurs in the context of dysregulation of multiple pathways. In this study, we investigated the ability of prolactin to modulate carcinogenesis when co-expressed with the potent oncogene transforming growth factor α (TGFα) in bitransgenic mice. Prolactin and TGFα cooperated to reduce dramatically the latency of mammary macrocyst development, the principal lesion type induced by TGFα. In combination, prolactin and TGFα also increased the incidence and reduced the latency of other preneoplastic lesions and increased cellular turnover in structurally normal alveoli and ducts compared with single transgenic females. Bitransgenic glands contained higher levels of phosphorylated ERK1/2 compared with single TGFα transgenic glands, suggesting that this kinase may be a point of signaling crosstalk. Furthermore, transgenic prolactin also reversed the decrease in ERα induced by neu-related lipocalin-TGFα. Our findings demonstrate that locally produced prolactin can strikingly potentiate the car-cinogenic actions of another oncogene and modify ovarian hormone responsiveness, suggesting that prolactin signaling may be a potential thera-peutic target.
Obese women diagnosed with breast cancer have an increased risk for metastasis, and the underlying mechanisms are not well established. Within the mammary gland, adipose-derived stromal cells (ASCs) ...are heterogeneous cells with the capacity to differentiate into multiple mesenchymal lineages. To study the effects of obesity on ASCs, mice were fed a control diet (CD) or high-fat diet (HFD) to induce obesity, and ASCs were isolated from the mammary glands of lean and obese mice. We observed that obesity increased ASCs proliferation, decreased differentiation potential, and upregulated expression of α-smooth muscle actin, a marker of activated fibroblasts, compared to ASCs from lean mice. To determine how ASCs from obese mice impacted tumor growth, we mixed ASCs isolated from CD- or HFD-fed mice with mammary tumor cells and injected them into the mammary glands of lean mice. Tumor cells mixed with ASCs from obese mice grew significantly larger tumors and had increased invasion into surrounding adipose tissue than tumor cells mixed with control ASCs. ASCs from obese mice demonstrated enhanced tumor cell invasion in culture, a phenotype associated with increased expression of insulin-like growth factor-1 (IGF-1) and abrogated by IGF-1 neutralizing antibodies. Weight loss induced in obese mice significantly decreased expression of IGF-1 from ASCs and reduced the ability of the ASCs to induce an invasive phenotype. Together, these results suggest that obesity enhances local invasion of breast cancer cells through increased expression of IGF-1 by mammary ASCs, and weight loss may reverse this tumor-promoting phenotype.
The patellofemoral joint is an articulation between the patella and the femoral trochlea, which serves to increase the lever arm of the extensor mechanism. The stability of the patella within the ...trochlear groove is supported statically by the bony confines of the groove itself, as well as the medial patellofemoral ligament, and dynamically by the vastus musculature. Pathologic changes seen on magnetic resonance imaging (MRI) are frequently well correlated with findings found by arthroscopy at the time of surgery. Degenerative changes to the articular cartilage, osteochondral lesions and loose bodies, tears in the retinaculum, and the medial patellofemoral ligament can be seen in MRI and are well correlated with arthroscopy. In addition, other findings that may predispose an individual to injury or degenerative changes over time, such as patella alta and trochlear dysplasia, can also be assessed by MRI and observed arthroscopically.
PDF
