Puberty-specific promotion of mammary tumorigenesis by a high animal fat diet.

INTRODUCTION: Increased animal fat consumption is associated with increased premenopausal breast cancer risk in normal weight, but not overweight, women. This agrees with our previous findings in obesity-resistant BALB/c mice, in which exposure to a high saturated animal fat diet (HFD) from peripuberty through adulthood promoted mammary tumorigenesis. Epidemiologic and animal studies support the importance of puberty as a life stage when diet and environmental exposures affect adult breast cancer risk. In this study, we identified the effects of peripubertal exposure to HFD and investigated its mechanism of enhancing tumorigenesis. METHODS: Three-week-old BALB/c mice fed a low-fat diet (LFD) or HFD were subjected to 7,12-dimethylbenz[a]anthracene (DMBA)-induced carcinogenesis. At 9 weeks of age, half the mice on LFD were switched to HFD (LFD-HFD group) and half the mice on HFD were switched to LFD (HFD-LFD group). Tumor gene expression was evaluated in association with diet and tumor latency. RESULTS: The peripubertal HFD reduced the latency of DMBA-induced mammary tumors and was associated with tumor characteristics similar to those in mice fed a continuous HFD. Notably, short-latency tumors in both groups shared gene expression characteristics and were more likely to have adenosquamous histology. Both HFD-LFD and continuous HFD tumors showed similar gene expression patterns and early latency. Adult switch from HFD to LFD did not reverse peripubertal HFD tumor promotion. Increased proliferation, hyperplasia, and macrophages were present in mammary glands before tumor development, implicating these as possible effectors of tumor promotion. Despite a significant interaction between pubertal diet and carcinogens in tumor promotion, peripubertal HFD by itself produced persistent macrophage recruitment to mammary glands. CONCLUSIONS: In obesity-resistant mice, peripubertal HFD is sufficient to irreversibly promote carcinogen-induced tumorigenesis. Increased macrophage recruitment is likely a contributing factor. These results underscore the importance of early life exposures to increased adult cancer risk and are consistent with findings that an HFD in normal weight premenopausal women leads to increased breast cancer risk. Notably, short-latency tumors occurring after peripubertal HFD had characteristics similar to human basal-like breast cancers that predominantly develop in younger women.

Histological subtypes of lung cancer in Chinese males from 2000 to 2012.

OBJECTIVE: To characterize the histological and epidemiological features of male lung cancer patients in China. METHODS: The demographic and histological information about male lung cancer patients identified from 2000-01-01 to 2012-12-31, was collected from the Cancer Hospital of the Chinese Academy of Medical Sciences. Relative frequencies (RF) were estimated for major histological subtypes and compared according to the years of diagnosis and birth. RESULTS: The RF of adenocarcinoma (ADC) increased from 21.96% to 43.36% and the RF of squamous cell carcinoma (SCC) decreased from 39.11% to 32.23% from 2000 to 2012 in the 15 427 male lung cancer patients included in this study (Z=17.909, P<0.0001; Z=-6.117, P<0.0001). The RF of ADC increased from 28.72% in 2000-2004, 36.88% in 2005-2008 to 48.61% in 2009-2012 in patients born after 1960. The age-adjusted RF of ADC in 2007-2012 increased consistently in all the investigated areas. CONCLUSION: The increased RF of ADC in male lung cancer patients highlights the need for further investigation of the etiologic factors of these tumors. Smoke-free policies rather than modifying tobacco products should be enforced.

The severity of duodeno-esophageal reflux influences the development of different histological types of esophageal cancer in a rat model.

The mechanism through which each histological type of carcinoma arises from the esophageal mucosa remains unknown. This study was designed to investigate whether there is an association between the severity of duodeno-esophageal reflux and the histological type of esophageal cancer. A series of 120 male Fischer rats, weighing ∼180 g, were randomized to receive one of the following procedures: duodeno-forestomach reflux (DFR) with reduced exposure to duodenal contents, duodeno-esophageal reflux (DER) with increased exposure to duodenal contents and three control operations (DFR, DER control and sham). The reflux of bile was estimated with (99m)Tc-PMT scintigraphy. All animals were fed a standard diet without carcinogen. The esophageal mucosa was assessed 50 weeks after surgery for carcinoma. The median scanned fraction rate of duodeno-esophageal reflux was significantly lower for the rodents in the DFR group than those in the DER group. Five of 28 rodents in the DFR group and 17 of the 22 rodents in the DER group developed esophageal carcinoma. None of the controls developed carcinoma. The five rodents in the DFR group developed SCC. Of 22 esophageal carcinomas for the DER group, nine were SCC, 12 ADC and one was adenosquamous carcinoma. The fraction of esophageal SCC for the DFR group was significantly higher than that for the DER group, while the fraction of esophageal ADC for the DFR group was significantly lower than that for the DER group. These observations suggest that the severity of duodeno-esophageal reflux in rodents is related to the development of different histological types of esophageal carcinoma.

What is hiding behind the pessary?

Vaginal pessaries are routinely used for initial management of pelvic organ prolapse and for women who are poor surgical candidates. Serious complications of long-term use without routine follow-up include erosion into surrounding organs and the development of fistulas. It is unclear however, if long-term use and chronic irritation could potentially contribute to development or delay the diagnosis of vaginal or cervical cancers. A 72-year-old Caucasian woman with a vaginal pessary retained for 3 years, who presented with leukocytosis and coagulopathy, was discovered to have stage II vaginal adenosquamous carcinoma upon surgical pessary removal. Chronic irritation and lack of follow-up with pessary use may contribute to masking the development and delaying the diagnosis of vaginal cancer in women with risk factors. Pessary use requires frequent follow-up to prevent complications.

Cervical cancer: prevention and treatment.

Cervical cancer is the commonest cancer cause of death among women in developing countries and efforts to prevent the disease using newer approaches and HPV vaccination need to be explored. Detection of cervical cancer at an early stage is associated with excellent survival but most women in developing countries present with advanced and often untreatable disease, with very poor survival. The ratio between incidence and mortality from cervical cancer remains very high, largely due to lack of access to appropriate anti-cancer therapies in developing countries. In developed countries with functional screening programs, cervical cancer has been rendered a relatively rare disease. Ongoing efforts to refine the characteristics of screening tests continue, as does implementation of current HPV vaccines for the primary prevention of cervical cancer.

High prevalence of multiple human papillomavirus infection in Japanese patients with invasive uterine cervical cancer.

OBJECTIVE: Multiple human papillomavirus (HPV) infection of the uterine cervix has been suggested as a risk factor for persistent HPV infection, resulting in the development of invasive cervical cancer. The aim of this study was to reveal the actual state of multiple HPV infection in Japanese patients with invasive cervical cancer. METHODS: Sixty fresh-frozen invasive cervical cancer tissues were examined for genotyping of HPV. The presence of HPV genotypes was determined with an HPV-DNA array, which can discriminate 25 different HPV genotypes with high sensitivity and specificity. RESULTS: Among 60 samples, 59 (96.7%) were positive for HPV. The three common genotypes were HPV-16 (83.3%), HPV-18 (45.0%) and HPV-52 (28.3%). Multiple HPV infection was observed in 47 of 60 samples (78.3%), among which 42 were infected with more than one high-risk genotype (70.0%). Multiple high-risk HPV infection was significantly more prevalent in patients below 40 years old (14/15, 93.3%) than in patients 40 years of age and over (28/45, 62.2%). CONCLUSION: The HPV-DNA array is the preferred method to detect HPV genotypes. Multiple HPV infection in Japanese patients with invasive cervical cancer seemed to be more frequent than reported in the literature.

Human papillomavirus detection and genotyping on pelvic nodes in patients with synchronous gynecological malignancies: a tool for identifying the primary site of lymphatic spread?

INTRODUCTION: Synchronous gynecological tumors are uncommon. Identifying the primary site of lymphatic spread may be difficult. METHODS: Two women with synchronous squamous cervical and adenosquamous endometrial cancers (patient A) and squamous cervical and serous borderline ovarian tumors (patient B) entered retrospectively this study. Both patients had pelvic nodal metastases of unknown origin. Uterine cervix, endometrium, and lymph nodes were tested for human papillomavirus DNA using high-sensitive polymerase chain reaction, followed by oligonucleotide microarray for genotyping. RESULTS: Human papillomavirus 16 DNA was extracted from portio vaginalis and pelvic nodes of both women. Viral homology between cervical and lymph nodal lesions helped to identify the primary metastasizing tumors in both patients. CONCLUSIONS: Human papillomavirus testing on pelvic lymphatic tissue represents a feasible tool to detect the primary site of lymphatic spread in synchronous gynecological malignancies, when uterine cervix is involved.

The biology of incipient, pre-invasive or intraepithelial neoplasia.

Invasive tumors (cancers or malignant lesions) typically develop in the setting in which there is the presence of putative non-invasive lesions and the development of these non-invasive lesions frequently precedes the development of cancers. For some organs, such as the oral cavity, cervix and skin, the respective putative pre-invasive lesions can be observed over time and documented to progress to invasive lesions. However, for less readily observable lesions, such as those of the prostate, the progression of the pre-invasive lesions, e.g., prostatic intraepithelial neoplasia (PIN) and prostatic proliferative inflammatory atrophy (PIA) to prostatic cancer are more difficult to document. Thus, for most organ systems, specific pre-invasive neoplastic lesions have been proposed based upon the apparent observations of one or more of the following: 1) microinvasive disease developing from a pre-invasive neoplastic lesion, 2) the general association of the pre-invasive lesion with invasive lesions, 3) the subsequent development of invasive lesions following diagnosis of the pre-invasive lesion, 4) correlations of the molecular features of the putative pre-invasive lesion with the matching invasive lesions, and 5) reductions in the rate of cancer following removal of the pre-invasive lesion. When there are mixtures of pre-invasive lesions with actual cancers in the same case, some of the above specific associations are more difficult to make. Several terms have been used to describe pre-invasive lesions, many of which are now less useful as our knowledge of these lesions increases. It is now commonly accepted that these lesions are a features of the spectrum of neoplastic development and most are accepted as ``neoplastic lesions'' with associated molecular features, even though they may be reversible even if they have mutations in suppressor genes (e.g., p53) or are associated with viral etiologies (e.g., cervical intraepithelial neoplasia). The overall term, "pre-invasive neoplasia", seems to best describe these putative pre-invasive lesions. Thus, terms such as incipient neoplasia should be abandoned. The term "intra-epithelial neoplasia" with an associated grade, which has been developed for pre-invasive neoplastic lesions of the cervix, i.e. cervical intraepithelial neoplasia (CIN), seems to be a terminology that adds consistency across epithelial organs. Thus, adoption of these terms for the additional organ sites of pancreas (PanIN) and prostate (PIN) seems accepted. Less descriptive terms such as the degrees of dysplasia of the oral cavity and bronchopulmonary system and actinic keratosis and Bowen's disease of the skin might be better designated as oral intraepithelial neoplasia (OIN), pulmonary intraepithelial neoplasia (PulIN) and dermal intraepithelial neoplasia (DIN). The etiology of pre-invasive neoplasia is the etiology of the matching cancers. Some obvious initiating factors include exposure to the whole range of ionizing and non-ionizing radiation, tobacco abuse and a broad range of other carcinogens (e.g., benzene). A frequent initiation factor is the setting of long standing continuing damage, inflammation and repair (LOCDIR) which leads to early molecular features associated with neoplasia after about one year. An excellent example of this is ulcerative colitis (UC) in which dysregulation of microsatellite repair enzymes have been documented one year following diagnosis of UC. While the nomenclature, description, diagnosis and etiology of pre-invasive neoplasia has advanced, approaches to therapy of such lesions have not progressed adequately even though it has been identified that, for example, removal of polyps periodically from the colorectum, DCIS from the breast, and high grade CIN from the cervix, results in a reduction in the development of cancers of the colorectum, breast, and cervix, respectively. With the development of more molecularly targeted therapy with fewer side effects, preventive therapies may be more successfully targeted to pre-invasive neoplastic lesions.

[Autopsy case of von Recklinghausen's disease associated with lung cancer, gastrointestinal stromal tumor of the stomach, and duodenal carcinoid tumor].

A 58-year-old man with von Recklinghausen's disease was admitted for further investigation of right chest pain. Chest X-ray revealed multiple emphysematous bullae in both lungs and a tumor shadow in the right upper lobe. Bronchofiberscopy was performed, but an adequate specimen was not obtained. The tumor was diagnosed as a non-small-cell lung cancer with direct invasion to the adjacent rib. Although chemotherapy and radiotherapy resulted in decrease in tumor size, the tumor subsequently increased in size and the patient died 14 months after the first admission. Autopsy revealed multiple emphysematous bullae, poorly differentiated adenosquamous cell carcinoma of the lung, gastrointestinal stromal tumor of the stomach, and duodenal carcinoid tumor. This case suggests the possibility that von Recklinghausen's disease associated with emphysematous bullae is a risk factor for lung cancer. It has also been suggested that the genetic abnormality responsible for von Recklinghausen's disease increases the risk for various types of malignancy. Although von Recklinghausen's disease is reportedly associated with various malignant tumors, it is quite rare for von Recklinghausen's disease to be associated with triple non-neurogenic tumors. Careful observation is mandatory for patients with von Recklinghausen's disease.

[Clinical analysis of primary lung cancer with a thin-walled cavity to explain the mechanism of thin-walled cavity formation].

We report 8 rare cases of primary lung cancer which showed a thin-walled cavity on chest X-ray and CT. We analyzed 8 cases (7 men, 1 woman) of primary lung cancer with thin-walled cavities admitted to our hospital between 1995 and 2006. The subjects were aged between 45 and 84 years of age (median: 72 years old). The reason for detection was treatment for tuberculosis in 1 case, ileus owing to metastasis to the small intestine in 1 case and tension pnumathorax 1 case, while 5 cases had abnormal chest x-ray film shadows without symptoms. Histologically, there were 5 cases of adenocarcinoma, 2 of squamous cell carcinoma, and 1 of adenosquamous cell carcinoma. Though various reports on the mechanism of the development of thin-walled cavity formation have been made, we suggest that it mainly develops by a check-valve mechanism, based on evaluation of the clinical course.

Association between cigarette smoking and prognosis in locally advanced cervical carcinoma treated with chemoradiation: a Gynecologic Oncology Group study.

OBJECTIVE: To determine if smoking, a known risk factor for a number of cancers including cervical cancer, is associated with poor prognosis in patients with locally advanced cervical carcinoma treated with chemoradiation. METHODS: Patients with primary, previously untreated, histologically confirmed stage II-B, III-B or IV-A cervical carcinoma participated in a Gynecologic Oncology Group (GOG) phase III study (GOG 165) and were randomly allocated to receive radiation plus either cisplatin or 5-fluorouracil. Smoking behavior was ascertained using an administered questionnaire and by quantifying urine cotinine concentration. Disease progression was defined as a >or=50% increase in the cross product of the existing tumor compared with previous assessments. Patients were followed until death. RESULTS: Of 328 enrolled patients, 12 were ineligible, one was inevaluable for reported smoking status and 40 others were inevaluable for cotinine-derived smoking status. Among evaluable patients, 133 (42%) were reported smokers and 111 (40%) were cotinine-derived smokers. The kappa for agreement between the groups was 0.872 (P<0.01). Compared with non-smokers, median survival was 15 months shorter for reported smokers and 20 months shorter for cotinine-derived smokers (P<0.01). After adjusting for covariates, a significant increase in the risk of death (but not disease progression) was observed for reported smokers (hazard ratio [HR]: 1.51; 95% confidence interval [CI]: 1.01-2.27; P=0.04) and cotinine-derived smokers (HR: 1.57; 95% CI: 1.03-2.38; P=0.04). CONCLUSIONS: Smoking predicts worse overall survival in women with locally advanced cervical carcinoma treated with chemoradiation.

Mucoepidermoid variant of adenosquamous carcinoma arising in ovarian dermoid cyst: a case report and review of the literature.

A 40-year-old woman with mucoepidermoid variant of adenosquamous carcinoma arising in dermoid cyst in left ovary is presented. The patient was staged as IC. Total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and pelvic and para-aortic lymph node sampling were carried out. The disease recurred in postoperative 12th month. To our best knowledge, this is 12th case of adenosquamous carcinoma in dermoid cyst and third case of mucoepidermoid variant of adenosquamous carcinoma in the literature.

[Adenosquamous carcinoma of the lung (an analysis of 13 cases)]. / Akcigerin adenoskuamöz karsinomu (13 olgu nedeniyle).

Adenosquamous carcinoma of the lung is a rare disease. The biological behavior and clinicopathologic characteristics of this tumor have not been well described. In this study, we retrospectively evaluated 13 patients with adenosquamous carcinoma of the lung diagnosed at our center between January 2001 and May 2004. There were 12 males and 1 female whose ages ranged from 45 to 69 years, with a mean age of 55.9 years. Ten patients were smoker. The most frequent symptoms were chest pain and cough. Bronchoscopic examination detected that tumor was centrally located in four cases and was peripherally located in nine cases. Preoperative pathological diagnosis was squamous cell carcinoma in eight patients, non-small cell lung carcinoma in four patients and adenocarcinoma in one patient. One patient was in pathological stage IA, three patients in stage IB, one patient in stage IIA, two patients in stage IIB, five patients in stage IIIA, and one patient in stage IIIB. Twelve patients underwent resection (six, lobectomy; five, pneumonectomy; one, bilobectomy). Five of 12 patients received adjuvant therapy. Five patients died of disease within 3 and 21 months. Seven patients have had survival time between 9 and 31 months.

Endometrial cancer in polyps: a clinical study of 27 cases.

PURPOSE OF INVESTIGATION: To review risk factors, clinical presentation, diagnostic methods, and histopathologic findings in 27 cases of endometrial cancer in polyps. METHODS: A descriptive, retrospective study of 204 consecutive patients with endometrial carcinoma who were diagnosed at our institution between June 1998 to June 2001. Endometrial cancer arising in polyps occurred in 27 patients (13.2%) and accounted for 1.8% of 1492 endometrial polyps diagnosed during this period. RESULTS: Patients had a mean age of 62 years. All except one woman were postmenopausal. Three breast cancer patients were currently given tamoxifen. Metrorrhagia was the presenting symptom in 74% of cases, although 22% of patients were asymptomatic at the time of diagnosis. Ultrasonography performed in 22 patients showed images compatible with an endometrial polyp in 50% of cases, myoma in 5%, and inconclusive findings in 45%. The median endometrial thickness was 11 mm (range 4-33 mm). Diagnosis was made by aspiration-biopsy in 13 patients and by hysteroscopic endometrial sampling in 13 (in one patient endometrial carcinoma was incidentally found in the surgical specimen). All patients were in FIGO Stage IA. Endometrioid carcinoma was found in 81.5% of cases. Retroperitoneal metastases were not found in 25 patients undergoing pelvic lymphadenectomy, nor neoplastic growth in the specimens of six polypeptomies performed during hysteroscopy. All patients are free of relapse after a mean follow-up of 30 months. CONCLUSIONS: Postmenopausal women with endometrial polyps diagnosed by ultrasonography should undergo directed biopsies under hysteroscopic vision. The present series confirms the good prognosis of endometrial cancer in polyps.

[Reflux of duodenal or gastroduodenal contents induces esophageal carcinoma in rats].

We observed the sequential development of columnar lined epithelium associated with adenocarcinoma, squamous dysplasia related with squamous cell carcinoma and adenosquamous carcinoma which were induced by duodeno-esophageal or gastro-duodeno-esophageal reflux in rats. Wistar male rats, weighing approximately 250 g were employed. Animals received total gastrectomy and were reconstructed with esophago-jejunostomy, which causes unavoidable duodeno-esophageal reflux. The animals were sacrificed every 10 weeks after surgery until 50 weeks. Erosions and basal cell hyperplasia were observed in the lower esophageal squamous epithelium at 10 weeks after surgery. At 20 weeks, glandular structures featured with galactose oxidase-Schiff-positive staining (foveolar metaplasia) appeared in the basal layer of esophageal squamous epithelium. At 30 weeks, the glands developed and formed cysts which were stained with concanavalin A (pyloric glandular metaplasia) or/and high iron diamine and alcian blue (intestinal metaplasia). Since 40 weeks after surgery, esophageal carcinomas were found. As adenocarcinomas were surrounded by the columnar-lined epithelium, squamous cell carcinoma and adenosquamous carcinoma were accompanied by squamous dysplasia. Persistent duodeno-esophageal reflux can change the stem cells of squamous epithelium to make columnar-lined cells. As part of the sequence of events leading to the development of columnar-lined epithelium, foveolar metaplasia was observed followed by the appearance of pyloric glandular metaplasia and intestinal metaplasia. Chronic duodenal reflux induces the development of esophageal carcinoma not only adenocarcinoma also squamous cell carcinoma and adenosquamous carcinoma. These pathways of carcinogenesis were different dual patterns.

Thioproline inhibits development of esophageal adenocarcinoma induced by gastroduodenal reflux in rats.

Several epidemiological cohort studies have suggested that duodeno-gastroesophageal reflux per se induces Barrett's esophagus leading to increased risk of the development of esophageal adenocarcinoma (EAC). However, the exact causative factors behind EAC remain unclear. Recently, we designed a new duodenal contents reflux model which retained normal stomach function. In this model, duodenal contents flowed back into the esophagus and stomach resulting in repeated re-entry into the esophagus through the site of esophagojejunostomy. To elucidate the factors underlying the development of EAC, thiazolidine-4-carboxylic acid (thioproline, TPRO) was applied to the new reflux models as a nitrite scavenger and as a probe to detect reactive nitrogen species (RNS). Post-operatively, 31 animals were divided into two groups according to diet. Animals belonging to the control group were given normal diet (n = 18), while the TPRO group was given food containing 0.5% TPRO (n = 13). All esophageal sections in both groups were examined using hematoxylin and eosin staining and immunohistochemical analysis of inducible nitric oxide synthase (iNOS). EACs developed in 7 of 18 rats (38.9%) of the control group, whereas no EACs were detected in the TPRO group (Fisher's exact test, P < 0.05). Conversely, esophageal squamous cell carcinoma (ESCC) was detected in 1 of 18 rats (5.6%) of the control group and in 1 of 13 rats (7.7%) of the TPRO group. The incidence of ESCC was not significantly different between the two groups (P = 0.671). iNOS protein was overexpressed in Barrett's esophagus of both groups. The present results suggest that RNS such as nitric oxide and peroxynitrite and nitroso compounds derived from reflux of duodenal contents play an important role in the development of EAC, and that the primary causes of ESCC and EAC may differ.

Smoking and cervical cancer: pooled analysis of the IARC multi-centric case--control study.

BACKGROUND: Smoking has long been suspected to be a risk factor for cervical cancer. However, not all previous studies have properly controlled for the effect of human papillomavirus (HPV) infection, which has now been established as a virtually necessary cause of cervical cancer. To evaluate the role of smoking as a cofactor of progression from HPV infection to cancer, we performed a pooled analysis of 10 previously published case-control studies. This analysis is part of a series of analyses of cofactors of HPV in the aetiology of cervical cancer. METHODS: Data were pooled from eight case-control studies of invasive cervical carcinoma (ICC) and two of carcinoma in situ (CIS) from four continents. All studies used a similar protocol and questionnaires and included a PCR-based evaluation of HPV DNA in cytological smears or biopsy specimens. Only subjects positive for HPV DNA were included in the analysis. A total of 1463 squamous cell ICC cases were analyzed, along with 211 CIS cases, 124 adeno- or adeno-squamous ICC cases and 254 control women. Pooled odds ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression models controlling for sexual and non-sexual confounding factors. RESULTS: There was an excess risk for ever smoking among HPV positive women (OR 2.17 95%CI 1.46-3.22). When results were analyzed by histological type, an excess risk was observed among cases of squamous cell carcinoma for current smokers (OR 2.30, 95%CI 1.31-4.04) and ex-smokers (OR 1.80, 95%CI 0.95-3.44). No clear pattern of association with risk was detected for adenocarcinomas, although the number of cases with this histologic type was limited. CONCLUSIONS: Smoking increases the risk of cervical cancer among HPV positive women. The results of our study are consistent with the few previously conducted studies of smoking and cervical cancer that have adequately controlled for HPV infection. Recent increasing trends of smoking among young women could have a serious impact on cervical cancer incidence in the coming years.

Targeted expression of HGF/SF in mouse mammary epithelium leads to metastatic adenosquamous carcinomas through the activation of multiple signal transduction pathways.

Overexpression of hepatocyte growth factor (HGF), also called scatter factor (SF), and its receptor c-Met are associated with poor prognosis for cancer patients. In particular, breast cancer cells can produce HGF that acts in a paracrine as well as in an autocrine manner. Therefore, HGF and c-Met are putative targets for cancer therapy. To explore HGF/c-Met signaling in breast cancer, we have generated transgenic mice expressing HGF specifically in mammary epithelium under the transcriptional control of the whey acidic protein (WAP) gene promoter. WAP-HGF transgenic females developed hyperplastic ductal trees and multifocal invasive tumors after several pregnancies, some of which progressed to lung metastases. Tumors produced HGF and displayed phosphorylated c-Met, which correlated with increased Akt as well as c-myc activation. A high growth rate, as demonstrated by Ki67 nuclear antigen staining, and a lack of progesterone receptor were characteristic of the tumors. Immunohistochemical analysis revealed areas of osteopontin (Opn) expression in WAP-HGF tumors and lung metastases in agreement with a previously reported role for Opn in invasive growth. We suggest that these mice may serve as a new breast cancer model for the evaluation of the effects of unscheduled HGF expression in breast cancer.