Associations Between Dog Breed and Clinical Features of Mammary Epithelial Neoplasia in Bitches: an Epidemiological Study of Submissions to a Single Diagnostic Pathology Centre Between 2008-2021.

Mammary cancer is one of the most common neoplasms of dogs, primarily bitches. While studies have been carried out identifying differing risk of mammary neoplasia in different dog breeds, few studies have reported associations between dog breeds and clinical features such as number of neoplastic lesions found in an individual case or the likelihood of lesions being benign or malignant. Such epidemiological studies are essential as a foundation for exploring potential genetic drivers of mammary tumour behaviour. Here, we have examined associations between breed, age and neuter status and the odds of a diagnosis of a mammary epithelial-origin neoplastic lesion (as opposed to any other histopathological diagnosis from a biopsied lesion) as well as the odds of a bitch presenting with either a single mammary lesion or multiple lesions, and the odds that those lesions are benign or malignant. The study population consisted of 129,258 samples from bitches, including 13,401 mammary epithelial neoplasms, submitted for histological assessment to a single histopathology laboratory between 2008 and 2021.In multivariable analysis, breed, age and neuter status were all significantly associated with the odds of a diagnosis of a mammary epithelial-origin neoplastic lesion. Smaller breeds were more likely to receive such a diagnosis. In cases diagnosed with a mammary epithelial neoplasm, these three factors were also significantly associated with the odds of diagnosis with a malignant lesion and of diagnosis with multiple lesions. Notably, while neutered animals were less likely to have a mammary epithelial neoplasm diagnosed, and were less likely to have multiple neoplasms, they were more likely to have malignant disease. Exploration of the patterns of risk of developing malignant disease, or multiple lesions, across individual breeds showed no breed with increased odds of both outcomes. Breeds with altered odds compared to the Crossbreed baseline were either at increased risk of malignant disease and decreased risk of multiple lesions, or vice versa, or they were at significantly altered odds of one outcome with no change in the other outcome. Our analysis supports the hypothesis that age, neuter status and intrinsic biological and genetic factors all combine to influence the biological heterogeneity of canine mammary neoplasia.

Epidemiology of canine mammary tumours on the Canary Archipelago in Spain.

BACKGROUND: Mammary gland tumours are the most frequently diagnosed tumours in the female dogs but just a few studies have analysed their epidemiology. Therefore, we set out to describe the epidemiology of canine mammary cancer in the Canary Archipelago, Spain. We analysed a pathology tumour registry (PTR) and identified 7362 samples obtained from 5240 female dogs resident on the Canary Archipelago during an 18-year period (2003-2020). Using a case-control study design, we compared mammary tumour affected dogs with the Canarian canine population registry in order to elucidate the breed associations for these tumours. RESULTS: The frequency of a diagnosis of mammary tumours relative to all tumour diagnoses in female dogs decreased during the study period from 62.7% to 48.9%. Contemporaneously, the proportion of dogs diagnosed with mammary tumours who were also neutered increased from 13.6% to 26.9%. There was a negative correlation (R = -0.84) between these changes. Additional findings were that: the proportion of female dogs diagnosed with multiple tumours increased by 23.5% and that the proportion of malignant tumours 89.2% diagnosed has remained stable through the period. Benign mammary tumours were diagnosed at younger ages (9.2 years old) than carcinomas (9.7 years old) and sarcomas (10.4 years old). Epithelial mammary tumours were diagnosed at younger ages in entire female dogs. Samoyed, Schnauzer, Poodle, German Pinscher and Cocker Spaniel were the breeds with the highest odds-ratios (OR) in comparison with the reference (crossbreeds) while Miniature Pinscher, American Staffordshire Terrier, English Pointer as well as some local breeds such as the Canary Warren Hound and the Majorero had the lowest ORs. CONCLUSIONS: This study provides a description of the changing epidemiology of canine mammary cancer in the Canary Archipelago over the last two decades. We found high rates of CMT with a significant predominance of malignant tumours. Exact risk factors are uncertain, but a combination of environmental, regional socioeconomic affecting human and their pets, and animal management factors are likely to play a part. Specifically, neutering was negatively associated with the proportion of epithelial mammary gland tumours and breeds native to the region were at lower risk of mammary tumours. A deeper analysis of all these factors will facilitate a deeper understanding of the epidemiology of mammary gland tumours in both the canine and the human population.

Canine mammary gland disease in New Zealand: a review of samples from 797 dogs.

AIMS: To evaluate the proportions of canine mammary gland lesions submitted to a New Zealand diagnostic laboratory, that were neoplastic vs. non-neoplastic and, among neoplasms, malignant vs. benign, and to determine whether age, reproductive status or breed of dog, or size of the mammary mass were associated with the histological diagnosis. METHODS: Canine mammary gland biopsies submitted between the start of 2012 and the end of 2016 were selected from the surgical biopsy database of IDEXX Laboratories, NZ. For each case, details on age, breed, and reproductive status of the patient were registered as reported by the submitting veterinarians, along with the size (classified as small, medium or large) of the lesion and the histological diagnosis reported by the pathologists. χ2 tests and independent sample t-tests were performed to evaluate associations. RESULTS: Samples (n = 895) were submitted from 797 dogs, of which 673 had mammary neoplasms while 124 had non-neoplastic lesions. Neoplasms composed of a single nodule were found in 591/673 (87.8%) dogs, while 82/673 (12.2%) dogs had multiple nodules. Of the total 771 neoplasms, 432 (56.0%) were histologically malignant, while 339 (44.0%) were benign. Among malignancies, the most common histological sub-types were simple carcinoma (160/771; 20.8%), complex carcinoma (54/771; 7%), and ductal carcinoma (32/771; 4.2%), while benign mixed mammary tumour (128/771, 16.6%) and complex adenoma (105/771; 13.6%) were the most frequently reported benign mammary neoplasms. There was no evidence of a difference in age (p = 0.09) or reproductive status (p = 0.79) of the dog or the size of the mass (p = 0.21) between neoplastic and non-neoplastic lesions. However, neoplastic mammary gland lesions were more frequent in purebred dogs (612/671; 91.2%) than crossbred dogs (61/126; 48.4%; p < 0.001). There was no evidence of a difference in age (p = 0.15) reproductive status (p = 0.36) or breed (p = 0.45) of dog between malignant and benign neoplasms. There was an association between size and histological benign or malignant status of a neoplasm (φ = 0.65, p < 0.001). CONCLUSIONS: Most canine mammary gland samples submitted for examination were neoplastic with slightly more malignant than benign lesions. Masses submitted from purebred dogs were more likely to be neoplastic, while large neoplasms were more likely to be malignant. CLINICAL RELEVANCE: The present findings provide the first description of the distribution of mammary gland lesions in a relatively large number of dogs in New Zealand, representing a preliminary investigation of canine mammary gland diseases in this country.

A Comparative Review of Mixed Mammary Tumors in Mammals.

Mixed tumors are characterized by the histological identification of two or more cell types. Commonly, a mixture of epithelial and myoepithelial cells is included in abundant stroma, which can consist of myxoid, chondroid or bony matrices. Spontaneously arising mixed tumors are rare lesions in the human breast but are common in human salivary glands and canine mammary glands. Subtle histopathological characteristics and overlapping attributes of malignant lesions with other benign lesions can lead to a diagnostic challenge. Mixed tumors can present as benign or malignant. While malignant mixed tumors are quite rare in the human breast they have a poor prognosis. Benign mixed mammary tumors occur more frequently in female dogs than in humans and are usually associated with a good prognosis. This review will provide a comprehensive overview of mixed mammary tumors, across various mammalian species.

High prevalence of benign mammary tumors in a rat model of polycystic ovary syndrome during postmenopausal period.

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in reproductive-age women. Significant associations between PCOS and benign breast diseases (BBD) and a possibly potential association between PCOS and breast cancer have been reported. The etiology of these events of mammary glands in PCOS remains unclear. Animal models that show BBD and breast cancer may contribute to further understanding about these diseases. We aimed to examine the spontaneous occurrence of mammary tumors, their prevalence, and type in our rat model of PCOS. Prenatal androgen-induced PCOS rats and controls were examined in later life. Benign mammary tumors were observed in 75% and 33.33% of PCOS rats and controls during the postmenopausal period, respectively (p = .0158). Mammary tumors were non-invasive, margins of excision were normal and tumors were freely movable, in both groups. After microscopic evaluations of tumors, proliferative breast lesions and adenomas with a tubular growth pattern were observed in both groups. However, in PCOS rats, of benign tumors two had a mixed pattern of fibroadenoma/fibroma and cysts. High prevalence of benign mammary tumors was observed in our rat model of PCOS during the postmenopausal period, possibly due to hormonal imbalances during their reproductive lifespan; this model may contribute to current data available regarding the events of mammary glands in PCOS.

Canine Spindle Cell Mammary Tumor: A Retrospective Study of 67 Cases.

Canine spindle cell mammary tumor (CSCMT) is an infrequent canine mammary tumor (CMT) composed of spindle or fusiform cells, which represents a challenge for pathologists and clinicians. Mammary tumors submitted for histopathology from 1998 to 2013 and compatible with CSCMTs were retrospectively selected. The tumors were diagnosed based on the hematoxylin and eosin (HE)-stained section; malignant tumors were graded using a canine soft tissue sarcoma grading scheme and a canine mammary tumor grading scheme, and they were further assigned a diagnosis based on immunohistochemistry (IHC) for pancytokeratin, cytokeratin 14, p63, calponin, vimentin, Ki-67, CD31, desmin, myosin, smooth muscle actin, glial fibrillary acidic protein, and S-100. The origin of the tumors was assessed as mammary, skin, or unknown. The prevalence of CSCMT was 1% of all CMTs. CSCMTs included 3 benign tumors (1 angioma and 2 benign myoepitheliomas) and 67 malignant tumors that after IHC were diagnosed as malignant myoepithelioma (64%), carcinoma and malignant myoepithelioma (19%), hemangiosarcoma (8%), undifferentiated sarcoma (5%), peripheral nerve sheath tumor (3%), and fibrosarcoma (2%). The diagnosis based on the HE-stained section differed from the diagnosis after IHC in 75% of the malignant cases. The majority of malignant CSCMTs were solitary (57%) large tumors (6.42 ± 3.92 cm) with low metastatic potential and high survival rate (8% tumor-related mortality). Higher sarcoma grade was associated with older age (P = .034) and greater tumor size (P = .037). Malignant CSCMTs need to be evaluated by IHC to ensure the histotype and the relatively benign clinical behavior, despite their large size.

Analysis of a new histological and molecular-based classification of canine mammary neoplasia.

Canine mammary tumors (CMTs) are morphologically and biologically heterogeneous, prompting several attempts to classify such tumors on the basis of their histopathological characteristics. Recently, molecular-based analysis methods borrowed from human breast cancer research have also been applied to the classification of CMTs. In this study, canine mammary neoplasms (n = 648) occurring in Korea from 2008 to 2011 were analyzed according to the histological classification and grading system proposed by Goldschmidt et al. Furthermore, randomly selected mammary carcinomas (n = 159) were classified according to the molecular subtype using immunohistochemical characteristics. Canine mammary neoplasia accounted for 52.6% (648/1250) of the tumors in female dogs, and 51.7% (340/648) of these were malignant. All of the carcinoma-anaplastic subtypes were grade III tumors (5/5, 100%), while most of the carcinoma-tubular subtypes (15/18, 83.3%) and carcinoma arising in a complex adenoma/mixed-tumor subtype (115/135, 85.2%) were grade I tumors. Tumor cell invasion into lymphatic vessels was most common in the comedocarcinoma, carcinoma-anaplastic, and inflammatory carcinoma subtypes. The most frequently occurring molecular subtype (70/159, 44%) was luminal A. However, the basal-like subtype was the most malignant and was frequently associated with grade III tumors and lymphatic invasion. The carcinoma-solid subtypes were also often of the basal-like subtype. Reclassification of CMTs using the newly proposed histopathological classification system and molecular subtyping could aid in determining the prognosis and the most suitable anticancer treatment for each case.

Superovulation does not affect the endocrine activity nor increase susceptibility to carcinogenesis of uterine and mammary glands of female offspring in mice.

PURPOSE: To evaluate the dual effects of superovulation on the endocrine activity and susceptibility to carcinogenesis of uterine and mammary glands of female offspring in mice METHOD: The mice were superovaluted. The relative uterine weight, ERα protein expression, and endocrine activity of female offspring (F1 generation and F2 generation) were measured. Furthermore, proliferative lesion of uterine and mammary glands of female offspring (F1 generation and F2 generation) was assessed by histopathologic examinations. RESULTS: There were no significant differences in relative uterine weight, ERα protein expression, incidence of proliferative lesion in mammary glands, and incidence of atypical hyperplasia, adenocarcinoma, and squamous metaplasia in uterine among the offspring (F1 generation and F2 generation) in each group. Likewise, there were no significant intergroup differences in the serum levels of sex related hormones. CONCLUSIONS: No significant alterations were found in the endocrine activity and susceptibility to carcinogenesis of uterine and mammary glands of female offspring in mice produced by superovaluted oocytes compared with those of naturally conceived offspring.

Epidemiology and classification for canine and feline mammary gland tumors: a histopathological survey of 437 mammary gland tumor biopsies performed in a secondary care hospital in Chiang Mai, Thailand from 2012 to 2019.

Background: Metastatic disease resulting from mammary gland tumors (MGTs) is a known cause of death among dogs and cats. Keys to successful prevention and management strategies involve the accurate recording of diagnostic data. Methods: This retrospective study reviewed the epidemiology and classification of canine mammary gland tumors (CMTs) and feline mammary gland tumors (FMTs), as well as the factors including sex, age, and breed related to the occurrence of these tumors. Accordingly, 1,736 tumor biopsy cases were reported from 2012 to 2019 at Chiang Mai University Small Animal Hospital, Thailand, with 1,639 canine tumor biopsy cases and 97 feline tumor biopsy cases. Results: The proportion of CMTs was reported at 24.5% (401/1,639) for all canine tumor biopsy cases. Benign and malignant tumors were reported at 14.5% (58/401) and 85.5% (343/401) for all CMT cases, respectively. The mean age of dogs affected by benign CMTs was 9.0 ± 3.0 years, which was significantly lower than for malignant CMTs at 9.9 ± 2.8 years (P = 0.0239). According to histopathological classification, benign mixed tumors and simple carcinoma types were highest among benign and malignant CMT cases, respectively. Moreover, female dogs were at significantly higher risk of developing mammary gland tumors (OR = 45.8, 95% CI [3.9-86.0], P < 0.0001) than male dogs, as well as older dogs (>8 years) (OR = 1.7, 95% CI [1.2-2.2], P = 0.0001) compared to young ones (≤8 years). The proportion of FMTs was 37.1% (36/97) for all feline tumor biopsy cases. Benign and malignant tumors for all FMTs were reported at 16.7% (6/36) and 83.3% (30/36), respectively. According to histopathological classifications, adenoma and simple carcinoma were present in the highest proportion among benign and malignant FMTs, respectively. Female cats were at a significantly higher risk of developing mammary gland tumors than male cats (OR = 25.7, 95% CI [3.9-272.8], P < 0.0001). Conclusions and clinical importance: There was a high proportion of MGT cases compared with other tumor cases reported in a secondary care hospital in Chiang Mai, Thailand from 2012 to 2019, and malignant tumor biopsies have been more frequently observed than benign tumor biopsies in both CMT and FMT cases. The resulting data originating from this study can be an aid for veterinary oncologists in better educating clients and planning treatment and prevention strategies and it can be used as a basis for further experimental studies in the oncology section.

Occurrence of mammary gland tumours in male dogs and its weak association with development of testicular tumours: a review.

Mammary gland tumours (MGTs) are commonly occurring neoplasms in female dogs. However, rare cases of MGTs in male dogs have been reported for years. Due to the low incidence of MGTs in male dogs in comparison to female dogs, veterinary oncology is mainly focused on mammary neoplasms diagnosed in female dogs and extensive research is conducted in this scientific area. Therefore, there are no sufficient epidemiological data on male dogs and the aetiology of their tumour development is still poorly understood.The aim of this literature review was to present cases of MGTs in male dogs for better understanding the scale of the problem over the years. The analyses of 74 affected male dogs with 92 tumours showed that the majority of MGTs in male dogs were benign tumours (54.3%), especially in form of adenomas, often developed in posterior canine mammary glands (58.1%).The increased number of canine MGTs in male dogs aged 7 -13 years with an age peak at 11 years was noted. The age of affected animals was not related to breed. Mammary gland neoplasms were diagnosed predominately in Crossbreeds (20.2%) followed by Cocker Spaniels (18.9%) and German Shepherds (10.8%).The association between MGT development in male dogs and co-occurrence of testicular tumours (TTs) has been discussed for years. Thus, cases of development of both tumours were included in this study. As a result, only in 12.7% cases of MGTs also history of TTs was described. Therefore, no general association between these tumours should be assumed.

The incidence of breast tumor during experimental hyperthyroidism.

The incidence of breast tumor in inbred C3H-A mice (virgin female) from hyperthyroid, hypothyroid, and euthyroid control groups at week 44 of the experiment was 86.67, 30, and 62.5%, respectively. The percentage of metastatic lymph nodes in these groups was 65.9±16.7, 35.9±5.9, and 53.9±7.2%, respectively (p<0.005). It was shown that hyperthyroidism was associated with increased incidence and aggressiveness of breast tumor, while hypothyroidism was associated with lower incidence of breast tumor in comparison with the control.

Epidemiology of mammary tumours in bitches under veterinary care in the UK in 2016.

BACKGROUND: There is limited information on the epidemiology of canine mammary tumours. This study aimed to estimate the incidence and risk factors for mammary tumours in UK bitches. METHODS: A nested case-control study was conducted within VetCompass to estimate the frequency and risk factors for clinically diagnosed mammary tumours during 2016 (VetCompass study). A second case-control study explored further breed associations for cases confirmed histopathologically compared to the VetCompass controls (laboratory study). Multivariable logistic regression was used to evaluate associations between risk factors and mammary tumours. RESULTS: The incidence of mammary tumours was 1340.7/100,000 per year (95% confidence interval: 1198.1-1483.3). A total of 222 clinical cases (VetCompass study) and 915 laboratory cases (laboratory study) were compared to 1515 VetCompass controls in the two analyses. In the VetCompass study, Springer and Cocker Spaniels, Boxers, Staffordshire Bull Terriers and Lhasa Apsos had increased odds of developing mammary tumours. Neutering was associated with reduced odds, while odds increased with increasing age and a history of pseudopregnancy. In the laboratory study, increasing age was associated with greater odds of mammary tumours, and the breeds most at risk were similar to those identified in the VetCompass study. LIMITATIONS: The timing of neutering was not consistently available. Comparing laboratory cases to VetCompass controls provided only exploratory evidence for the breed associations identified. CONCLUSIONS: The study provides an update on the frequency of canine mammary tumours.

A review of the incidence and coincidence of uterine and mammary tumors in Wistar and Sprague-Dawley rats based on the RITA database and the role of prolactin.

Wistar rats are frequently selected for use in carcinogenicity studies because of their advantageous survival rate, which is more favorable than other strains such as the Sprague-Dawley (SD) strain. Uterine and mammary tumors are relatively common spontaneous neoplasms of both strains. We examined the incidence and coincidence of uterine tumors and mammary tumors in control animals of both strains within the RITA database. There was a strong inverse relationship between these tumor types in Wistar rats (p < .001). A less strong relationship was present in SD rats (p = .057). This association is likely to be related to prolactin. A short review of the role of prolactin in rats is given. These results are also discussed in the background of nonspecific toxicity at high dose levels in carcinogenicity studies above MTD levels resulting in reduction in body weights of >10%.

Breed variations in the incidence of pyometra and mammary tumours in Swedish dogs.

Dogs enrolled in a Swedish insurance company (during 1995-2006) were studied for development of pyometra and mammary tumours (MTs), with special attention to breed and age. There were over 260,000 female dogs with over 1,000,000 dog-years at risk (DYAR) in the database, using data on bitches up to 10 years of age and 110 breeds with over 1000 DYAR. In total, 20 423 bitches were diagnosed with pyometra and 11,758 with MTs and 30,131 with either or both of the two diseases. The incidence rate (IR) for pyometra was 199 (95% CI 196-202), for MTs 112 (95% CI 110-114) and for either or both of the two diseases 297 (95% CI 294-301) dogs per 10,000 DYAR. The mean age of diagnosis pyometra was 7.0 years (SD ± 2.2), MTs 8.0 years (SD ± 1.6). In all breeds, the overall proportion of the bitches that developed disease by 10 years of age was for pyometra 19%, MTs 13%, and either or both of two diseases 30%. The top 10 breeds diagnosed with either or both of the two diseases were the Leonberger (73%), Irish Wolfhound (69%), Bernese Mountain Dog (69%), Great Dane (68%), Staffordshire Bull Terrier (66%), Rottweiler (65%), Bullterrier (62%), Doberman (62%), Bouvier des Flandres (60%), Airdaleterrier (60%). These data provide information of the combined disease incidence in a large number of different breeds. Breed variations in incidence rate suggests genetic components in disease development. Our study may be valuable in the search for genetic risk-factors or protective factors.

Canine mammary tumours, an overview.

Canine mammary tumours (CMTs) are the most common neoplasms in intact female dogs. Although the prevalence of these tumours decreases in regions where preventive ovari(ohyster)ectomy is performed, it remains an important disease entity in veterinary medicine. Moreover, treatment options are limited in comparison with human breast cancer. Nevertheless, recent human treatment protocols might have potential in bitches suffering from CMTs.

Profile of early occurring spontaneous tumors in Han Wistar rats.

It is sometimes difficult to assess the relevance of tumors that occur in treated animals in short-term studies. This report is intended to establish a general profile of tumor occurrence in young Han Wistar rats. Data were collected and evaluated from 29 rat carcinogenicity studies and from a few 2-, 4-, 13-, and 26-week studies conducted between 1995 and 2009 at Huntingdon Life Sciences, UK. The route of administration was dietary, oral gavage, or inhalation, and the analysis was confined to sporadic deaths (decedents) in carcinogenicity studies. In Han Wistar rats, the most common and earliest occurring tumor was malignant lymphoma in both sexes, the earliest being seen in the 16th and 26th week in males and females, respectively. The incidence of malignant lymphoma was slightly higher in males than in females. The second most common type of tumor was brain tumors in males and mammary tumors in females. Compared with Sprague-Dawley rats, where the most common early tumor was pituitary tumor in females, the most common early tumor in Han Wistar rats was malignant lymphoma in both sexes. These early tumor profiles are consistent with the lifetime tumor occurrence in these strains.

[Pros and cons of gonadectomy in female and male cats]. / Vor- und Nachteile der Kastration von Kätzinnen und Katern.

Gonadectomy irreversibly prevents reproduction by removing germ cells as well as gonadal hormones. Moreover, consequences of gonadectomy include metabolic alterations influencing the incidence of diseases, phenotype and behavior. The desirable and undesirable effects of castration on different organ systems and their relation to timing of gonadectomy are discussed. For reasons of disease prevention as well as ease of husbandry and control of pet overpopulation prepuberal castration of non-breeding cats is recommended. At the time of gonadectomy the risk for developing obesity and associated diseases as well as dietary measures should be discussed with the owner.

Role of body condition score and adiponectin expression in the progression of canine mammary carcinomas.

Obesity has been identified as a risk factor for developing breast cancer in post-menopausal period in humans and has been suspected to be associated with a worse prognosis also in the bitch. The aims of this study were to investigate the association between body condition score (BCS) and the prognosis of canine mammary carcinomas (CMCs) and the relationships between adiponectin expression and tumour behaviour. Seventy-three bitches with tubular, tubulopapillary, solid or complex carcinomas were included in the present study. For each dog, evaluation of BCS was conducted using a nine-point BCS system and the study population was divided into normal weight (4-5/9 points; n = 42), overweight (6-7/9 points; n = 19) and obese (8-9/9 points; n = 12). Type of diet (commercial, homemade or mixed) was recorded. After surgical excision, histological type, tumour size and nodal status were assessed and adiponectin expression was determined and quantified by immunohistochemistry and morphometric analysis. CMC histotype was not correlated with BCS, while a positive correlation between BCS and histological grade (p < .01) was observed. Overweight and obese bitches combined showed a shorter cancer-specific survival than normal weighted bitches (p < .01). Bitches fed with a homemade diet had a higher BCS than dogs fed with a commercial one, although no relationship was observed between diet and  cancer-specific survival. Thirty-six CMCs scored positive for adiponectin expression (49%), but no correlation was found between the hormone expression and either CMC characteristics or prognosis. In conclusion, a higher BCS seems to be related with a higher prevalence of more aggressive CMCs and negatively affects the survival time in bitches with these mammary tumours.

Mammary tumor phenotypes in wild-type aging female FVB/N mice with pituitary prolactinomas.

Prolactin-secreting pituitary adenomas are common spontaneous lesions in aging FVB females. Prolactin-secreting pituitary proliferations play a significant role in mouse mammary tumorigenesis generally producing adenosquamous carcinomas. Since genetically engineered FVB mice are frequently used to study mammary tumor biology, we have examined a cohort of 64 aging wild-type FVB/N females to establish the prevalence and the nature of spontaneous mammary and pituitary tumors. Tissues from mammary and pituitary glands were studied by histopathology and immunohistochemistry. Of the 64 examined mice, 20 had pituitary tumors and 20 had mammary tumors. Mammary and pituitary tumors were associated in 17 mice. All pituitary tumors were prolactin-positive by immunohistochemistry and classified as prolactinomas. Fourteen mammary tumors, including 12 cases with and 2 without concurrent prolactinomas, were adenocarcinomas with different combinations of epithelial growth patterns. Five mice with prolactinomas had mammary tumors characterized by the epithelial-mesenchymal transition (EMT) phenotype. Estrogen receptor alpha (ERalpha)-positivity was observed for 14 of the 18 mammary tumors tested, including both adenocarcinomas with nuclear immunoreactivity and EMT-phenotype tumors with both nuclear and cytoplasmic immunoreactivity. No immunoreactivity for the progesterone receptor was observed. This study confirms that spontaneous prolactinomas and mammary tumors are both common and significantly associated lesions in FVB mice. Parity and age represented risk factors for the development of these tumors. Compared with previous reports, prolactinoma-associated mammary tumors displayed a broader morphologic spectrum, including cases with the EMT phenotype. The elevated number of prolactinoma-associated and ERalpha-positive mammary tumors opens intriguing possibilities concerning the role of ERalpha cytoplasmic localization during EMT tumorigenesis.

High maternal milk intake in the postnatal life reduces the incidence of breast cancer during adulthood in rats.

Environmental factors during perinatal life can lead to changes in the mammary gland, making it susceptible to cancer in adulthood. Breastfeeding has a special importance since it takes place at a critical period of growth and development of the newborn. We aimed to analyze if an appropriate lactation protects the offspring against mammary carcinogenesis during adult life and explore the mechanisms involved in the protective effect. One-day-old Sprague-Dawley female rats were randomly distributed in litters of three (L3), eight (L8) or 12 (L12) pups per dam, to induce a differential consumption of breast milk. At 55 days of age, the animals were treated with a single dose of dimethylbenzanthracene to study tumor latency, incidence and progression. Histological, immunohistochemical and Western blot studies were performed. We observed lower incidence and higher latency in L3 compared to the other groups. The mitotic index and expression of proliferating cell nuclear antigen (PCNA) was significantly augmented in tumors of L12 rats compared to L3 and L8, while the apoptotic index was augmented in tumors of L3 v. L12. Cleaved caspase 8 was significantly higher in tumors from L3 compared to L12. Tumors developed in L3 have a greater number of apoptotic bodies and a greater expression of caspase 8. These results demonstrate that the animals that maintained a higher intake of maternal milk (L3) presented lower incidence and greater tumor latency. Lower consumption of breast milk (L12) would increase tumor mitosis and the expression of PCNA, explaining the higher tumor incidence observed in this group.