The complex and often confusing history, histology and histogenesis of mesonephric, STK11 adnexal tumour and mesonephric-like neoplasms of the upper female genital tract (including broad ligament).

Mesonephric lesions in the female genital tract are uncommon, with those arising from the upper tract being much less frequent than those developing in the lower tract (mesonephric hyperplasia and carcinoma). The most common upper tract lesions include rete cyst/cystadenoma and female adnexal tumour of Wolffian origin (FATWO). The integration of morphological, immunohistochemical and molecular studies on FATWOs has enabled recognition of a novel entity, the STK11 adnexal tumour, which is often associated with Peutz-Jeghers syndrome (~50%) and frequently has a salivary gland morphology but an unknown origin. Similarly, 'mesonephric-like' adenocarcinoma, an entity with striking similarities to mesonephric carcinoma but currently favoured to be of Müllerian derivation based on its association with other Müllerian tumours and molecular findings, has also been recently described, and may histologically mimic both FATWOs and STK11 adnexal tumours. In this review, we provide a historical overview of upper female genital tract mesonephric proliferations and discuss mesonephric lesions, STK11 adnexal tumour, mesonephric-like adenocarcinoma, and mimickers, the most common being endometrioid carcinoma.

Callosal disconnection and limb-kinetic apraxia.

According to Liepmann, patients with limb-kinetic apraxia (LKA) have a loss of upper limb deftness-dexterity. Prior studies have revealed in right-handed patients that, whereas injury of the left hemisphere induces an ipsilesional LKA, injury to the right hemisphere does not induce an ipsilesional LKA. There are at least two possible means by which the left hemisphere may influence the deftness of the left hand, either by callosal connections or by ipsilesional corticospinal projections. The purpose of this study was to learn whether a patient with a focal lesion of the corpus callosum had a callosal disconnection LKA. This 57-year-old right-handed man had a memory impairment, and upon brain imaging, was found to have a septum pellucidum cyst, which was causing mild ventricular obstruction to the occipital and temporal horns. He underwent an endoscopic-assisted fenestration of the septum pellucidum. Postoperative imaging revealed a lesion of the mesial portion of his corpus callosum and an assessment of praxis revealed that he had both a limb-kinetic and ideomotor apraxia of his left but not his right hand. The observation that this man had a callosal disconnection LKA of his left hand suggests that in some people it is the left hemisphere's premotor or motor cortex that enables the right hemisphere's motor system to program deft movements of the left hand.

Impact + resistance training improves bone health and body composition in prematurely menopausal breast cancer survivors: a randomized controlled trial.

UNLABELLED: Our randomized controlled trial in prematurely menopausal breast cancer survivors showed that impact + resistance training prevented increases in percentage of body fat compared with controls and also improved BMD at the hip and prevented BMD loss at the spine among exercise-trained women who were menopausal for >1 year. INTRODUCTION: Cancer treatment-related menopause worsens bone health and body composition in breast cancer survivors (BCS). We investigated whether impact + resistance training could improve bone mineral density (BMD), reduce bone turnover, build muscle, and decrease fat mass in BCS with premature menopause. METHODS: We conducted a randomized controlled trial in 71 BCS (mean age, 46.5 years) within 5 years of treatment-related menopause. Women were randomly assigned to one of two groups: (1) impact + resistance training (prevent osteoporosis with impact + resistance (POWIR)) or (2) exercise placebo (FLEX) 3×/week for 1 year. Outcomes were hip and spine BMD (in grams per square centimeter) and body composition (percent body fat (%BF) and lean and fat mass (in kilograms)) by DXA and bone turnover markers (serum osteocalcin (in nanograms per milliliter) and urinary deoxypryrodinoline (in nanomoles per milliliter). RESULTS: There were no significant group × time interactions for bone outcomes when using an intent-to-treat approach on the full sample. In analyses restricted to BCS who were menopausal for ≥1 year, POWIR increased BMD at the hip and slowed BMD loss at the spine compared with FLEX (femoral neck-POWIR, 0.004 ± 0.093 g/cm(2) vs. FLEX, -0.010 ± 0.089 g/cm(2); p < 0.01; spine-POWIR, -0.003 ± 0.114 g/cm(2) vs. FLEX, -0.020 ± 0.110 g/cm(2); p = 0.03). POWIR prevented increases in %BF (POWIR, 0.01 % vs. FLEX, 1.3 %; p < 0.04). Women with attendance to POWIR at ≥64 % had better improvements in %BF than women attending less often (p < 0.03). CONCLUSION: Impact + resistance training may effectively combat bone loss and worsening body composition from premature menopause in BCS.

A prospective study of conventional transbronchial needle aspiration: performance and cost utility.

BACKGROUND: Conventional transbronchial needle aspiration (TBNA) is a cheap, minimally invasive tool for lung cancer staging and diagnosis. Endobronchial ultrasound-guided TBNA (EBUS-TBNA) is more sensitive but is more expensive and less widely available. We describe a prospective analysis of TBNA diagnostic, staging and cost utility in a centre in the UK. OBJECTIVES: To illustrate the potential diagnostic, staging and cost utility of a low cost conventional TBNA service. METHODS: A prospective analysis of 79 TBNA procedures over a 2-year period was performed looking at performance and cost utility in a 'mixed' cohort with variable pre-test probability of malignancy (year 1) followed by a high probability cohort (year 2). RESULTS: TBNA avoided mediastinoscopy in 25% of the cases overall (37% in high probability vs. 13% in the 'mixed' cohort, p = 0.03). The overall prevalence of malignancy was 84%, sensitivity 79%, negative predictive value 58% and accuracy 85%. Diagnostic utility varied with pre-test probability and nodal station. TBNA down-staged 8% of lung cancer patients to receive surgery and confirmed the pre-treatment stage (inoperability) in 74%. TBNA led to theoretical cost savings of GBP 560 per patient. CONCLUSIONS: TBNA can achieve a high diagnostic sensitivity for cancer in high probability patients and stage the majority appropriately, thereby avoiding unnecessary mediastinoscopies and reducing costs. It may also down-stage a minority to have surgery. TBNA is cheap, routinely available and learnable. As EBUS-TBNA will take time to develop due to its costs, all respiratory centres should perform TBNA at flexible bronchoscopy in suspected lung cancer with accessible mediastinal adenopathy.

Changes in lung cancer incidence in South Asians in Leicester, 1990-2005.

BACKGROUND: A previous study showed that lung cancer incidence in Leicester's South Asian (SA) population had increased between 1990 and 1999. We expanded the original data set to determine if this increase had continued in recent years. METHODS: All patients diagnosed with lung cancer in Leicester between 1990 and 2005 were identified. Ethnicity was assigned using Nam Pechan software, deprivation by Townsend score. Using Poisson regression, incidence rate ratios (IRRs) were calculated to assess variations in incidence by ethnicity, deprivation and period of diagnosis. RESULTS: Comparing patients diagnosed in 2000-2005 with those in 1990-1994, the risk of lung cancer increased in the SA men (IRR: 1.67 (95% CI: 0.99, 2.78)) whereas in the non-South Asian (NSA) men, it had fallen (IRR: 0.84 (95% CI: 0.76, 0.94)). Comparing patients diagnosed in 2000-2005 with those in 1995-1999 an increase continued in the SA men (IRR: 1.11 (95% CI: 0.71-1.74)). A significant rise was observed in the NSA women comparing those diagnosed from 2000-2005 to 1995-1999 (IRR: 1.16 (95% CI: 1.01, 1.33)). CONCLUSION: Lung cancer is an important public health issue amongst SAs in Leicester and has increased significantly since the early 1990s, with rates sustained in the more recent years of 2000-2005. Changes in the rates of lung cancer in SA and NSA populations are likely to be due to changing smoking habits.

Endobronchial ultrasound guided transbronchial needle aspiration.

Staging for non-small cell lung cancer (NSCLC) requires accurate assessment of the mediastinal lymph nodes which determines treatment and outcome. As radiological staging is limited by its specificity and sensitivity, it is necessary to sample the mediastinal nodes. Traditionally, mediastinoscopy has been used for evaluation of the mediastinum especially when radical treatment is contemplated, although conventional transbronchial needle aspiration (TBNA) has also been used in other situations for staging and diagnostic purposes. Endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA) offers a minimally invasive alternative to mediastinoscopy with additional access to the hilar nodes, a better safety profile, and it removes the costs and hazards of theatre time and general anaesthesia with comparable sensitivity, although the negative predictive value of mediastinoscopy (and sample size) is greater. EBUS-TBNA also obtains larger samples than conventional TBNA, has superior performance and theoretically is safer, allowing real-time sampling under direct vision. It can also have predictive value both in sonographic appearance of the nodes and histological characteristics. EBUS-TBNA is therefore indicated for NSCLC staging, diagnosis of lung cancer when there is no endobronchial lesion, and diagnosis of both benign (especially tuberculosis and sarcoidosis) and malignant mediastinal lesions. The procedure is different than for flexible bronchoscopy, takes longer, and requires more training. EBUS-TBNA is more expensive than conventional TBNA but can save costs by reducing the number of more costly mediastinoscopies. Revenue based tariff systems have been slow to reflect the innovation of techniques such as EBUS-TBNA. In the future, endobronchial ultrasound may have applications in airways disease and pulmonary vascular disease.

Investigating the diet of the omnivorous mirid Dicyphus hesperus using stable isotopes.

Omnivory involves numerous feeding relationships and a complex web of interactions. When using omnivores in biocontrol, these interactions need to be understood to maximize feeding on the target species and minimize non-target interactions. Dicyphus hesperus is used along with Encarsia formosa for biocontrol of whiteflies in greenhouse tomato crops. Dicyphus hesperus is a generalist omnivore which feeds on all components of the system. To quantify these interactions, stable isotope analysis was used to identify trophic position with nitrogen isotopes (delta15N) and plant sources with carbon isotopes (delta13C). Feeding trials were used to establish baseline isotopic data for D. hesperus and their diet, including Verbascum thapsus, an alternative plant food. Cage trials were used to monitor population abundances and the isotopic signature of D. hesperus. In feeding trials, D. hesperus were enriched relative to their food, suggesting an elevated trophic position. However, large amounts of isotopic variation were found within all diet components, with only V. thapsus exhibiting a distinct signature. In cage trials, the average delta15N and delta13C of the omnivore declined over time, coinciding with declines in total available prey, though it may be confounded by changes in temperature. The range of delta13C, but not the range of delta15N, also declined over time. This suggests a change in the plant source within the diet, but also some unquantified variability within the population. We suggest that diet variability exists within D. hesperus populations, declining as prey become less abundant.

Topology profile for a glutamate receptor: three transmembrane domains and a channel-lining reentrant membrane loop.

We investigated the transmembrane topology of the GluR3 subunit that was translated in rabbit reticulocytes supplemented with microsomal membranes. A prolactin reporter epitope was fused to GluR3 at six locations, bracketing each of the proposed transmembrane domains. The sidedness of the epitope in the microsomal membrane was then assessed by proteinase K sensitivity. The N terminus and the entire region between M3 and M4 was extracellular, and the C terminus was intracellular by this method. Four native N-linked glycosylation sites in the amino terminus and one introduced site between M3 and M4 were utilized, confirming the extracellular location of these regions. Epitopes inserted upstream and downstream of M2 were protease sensitive and thus intracellular. Our results support a topological model for glutamate receptor subunits that consists of three transmembrane domains, M1, M3, and M4, and another domain, the proposed channel-lining M2, which forms a reentrant membrane segment with both ends facing the cytoplasm.

Evaluation of cyclosporine-treated mice as hosts for growing and testing the chemosensitivity of first-transplant-generation human tumor xenografts implanted under the kidney capsule.

Freshly resected human tumors were grown as xenografts under the kidney capsules of conventional mice immunosuppressed by daily treatment with cyclosporine A (CsA; 60 mg/kg/day, sc). Tumor persistence and growth in CsA-treated mice were comparable to those found in nude mice. Lower doses or less aggressive schedules of CsA resulted in xenograft rejection. CsA (60 mg/kg/day, sc) treatment of mice was toxic but not lethal. It resulted in a 20% decrease in water consumption, a 10% loss in body weight, and significant reductions in thymus, kidney, and liver weights. Therapeutic doses of cancer chemotherapeutic agents were tolerated by CsA-treated mice, but 10% lethal doses were lethal in 100% of the mice. These results indicate that CsA-treated mice would be an economic alternative to nude mice for growing human tumor xenografts and for testing their chemosensitivity, with the caveat that the dose-limiting toxicity of cancer chemotherapeutic agents will be reached at lower doses in CsA-treated mice.

Opposite effects of different strains or batches of same strain of BCG on in vitro generation of syngeneic and allogeneic antitumor cytotoxicity.

Pretreatment of mice with three batches of BCG Phipps strain 10 days before in vitro immunization of their spleen cells with syngeneic or allogeneic tumor cells augmented the levels of antitumor cytotoxicity (compared to the levels exhibited by in vitro immunized spleen cells from normal mice), whereas pretreatment with another batch of BCG Phipps strain or with a batch of BCG Tice strain suppressed antitumor cytotoxicity. The suppressive effects of these BCG vaccines could not be attributed to route of administration, dose of BCG, or percentage of colony-forming units in an inoculum. The effect of the interval between BCG pretreatment and in vitro immunization on the generation of antitumor cytotoxicity was evaluated; one BCG batch was of special interest, inasmuch as augmented cytotoxicity was obtained when the interval was short and suppressed cytotoxicity was obtained when the interval was long.

Relationship of Bacillus Calmette-Guérin-induced suppressor cells to hematopoietic precursor cells.

Bacillus Calmette-Guérin (BCG) stimulated the proliferation of granulocyte-macrophage colony-forming cells (CFU) and activated suppressor cells that inhibit the immunization of T-lymphocytes in vitro. Increases in both CFU concentration and suppressor cell activity were moderate in the bone marrow and marked in the spleen of mice given BCG i.v. In the bone marrow, these increases were apparent 2 days after treatment with BCG, while in the spleen they did not occur until 7 days after BCG. A BCG strain that produced no increases in CFU concentration also produced no activation in suppressor cell activity. Fractionation of spleen cells through nylon wool and density gradients revealed that cell populations enriched in CFU were also enriched in suppressor cell activity. The paralelism in the response to CFU and suppressor cells to BCG indicates that there is a close relationship between these two cell populations.

Inhibition of estrogen-dependent breast cancer growth by a reaction product of alpha-fetoprotein and estradiol.

Reaction of picomolar quantities of human or rodent alpha-fetoprotein (AFP) with nanomolar quantities of 17 beta-estradiol (E2) generates a product of unknown structure, designated AFP/E2, that inhibits estrogen-stimulated growth of mouse uterus. We describe herein the effect of rodent AFP/E2 on the in vivo growth of two estrogen-dependent breast cancers, the MCF-7 human breast cancer and the MTW9A rat mammary cancer. Both cancers were grown as xenografts under the kidney capsule of cyclosporine-immunosuppressed male BDF1 mice. In addition, the MTW9A tumor was grown as a homograft in syngeneic ovariectomized Wistar-Furth female rats. Estrogen support was provided by s.c. Silastic E2 implants. Injecting AFP/E2 that was generated by incubating 1.0 microgram of AFP with 0.5 microgram of E2 for 1 h at room temperature resulted in cessation of growth and, in most cases, regression of MCF-7 tumor xenografts. It also produced regression of MTW9A tumor homografts and significantly inhibited growth of MTW9A xenografts. Treatment with AFP alone or E2 alone did not inhibit growth of these tumors. The data suggest that AFP/E2 has a unique property which causes attenuation or shut-down of the biochemical reactions through which estrogen-dependent tumor growth is mediated.

Evaluation of growth and histology of human tumor xenografts implanted under the renal capsule of immunocompetent and immunodeficient mice.

Fresh surgical explants of human carcinomas were implanted as first transplant generation xenografts under the kidney capsule of mice. Immunocompetent and immune-deficient mice were compared for their ability to support the persistence and growth of these xenografts. Consistent growth of tumor xenografts could not be demonstrated following implantation under the kidney capsule of immunocompetent mice. Immunological infiltration and rejection of the xenografts began 3 days postimplantation, and tumors were largely eliminated from the subcapsular space by 6 days postimplantation. In contrast human tumors consistently grew under the kidney capsule of nude mice. Significant growth became apparent by 9 days postimplantation with most human carcinomas and continued thereafter. Growth was always accompanied by neovascularization of tumor xenografts which was visible by examination of tumor-bearing kidneys under a dissecting microscope (X 6). There was no histological evidence of immunological interference with the persistence and growth of xenografts in nude mice. Thymectomized, irradiated, bone marrow-reconstituted conventional mice, as well as conventional mice, treated daily with 60 mg of cyclosporine A/kg were comparable to nude mice as hosts which supported the long-term persistence and growth of subrenal capsule implants of human tumors. Such mice could provide an alternative to nude mice as hosts in which chemosensitivity assays could be carried out against growing human tumors at a considerable saving in cost and convenience.

Correlation of in vitro and in vivo growth suppression of MCF-7 human breast cancer by 2,3,7,8-tetrachlorodibenzo-p-dioxin.

The purpose of this study was to compare the effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the in vitro and in vivo 17 beta-estradiol (E2)-dependent growth of MCF-7 human breast cancer cells. In culture, a major component of postconfluent growth of MCF-7 cells is E2 dependent. In vivo, MCF-7 cells fail to grow as xenografts without exogenous E2 support. Thus the effect of TCDD on postconfluent MCF-7 growth in culture was compared with its effect on MCF-7 xenograft growth in immunosuppressed mice. A concentration of 10(-9) M E2 was optimal for supporting postconfluent growth of MCF-7 cells in culture into multicellular aggregates (foci) on a monolayer background. The 50% inhibitory dose of TCDD under these conditions was 3 x 10(-10) M, while E2-dependent focus development was completely inhibited by 10(-8) M TCDD. Weekly i.p. administration of TCDD (5 micrograms/kg) to mice bearing MCF-7 tumor xenografts resulted in inhibition of the tumor growth rate for the first 2 weeks, followed by recovery to the control growth rate during the third week. These recovered tumors were found to retain estrogen-dependent growth as shown by second generation transplantation studies. The p.o. route of TCDD administration yielded a similar 2-week transient suppression of growth with a concentration of 8 micrograms TCDD/kg body weight but only a 1-week growth rate latency with a 2-microgram/kg body weight dose. A single 5-micrograms/kg dose given 1 day after implantation was virtually noninhibitory. These results indicate that TCDD suppression of estrogen-dependent MCF-7 human breast cancer cell growth in vitro was predicative of a similar growth suppression of MCF-7 solid tumor xenografts in vivo. However, additional host-related factors must be involved in vivo, since suppression of tumor growth is transient. These studies provide a basis for future in vivo investigations of TCDD endocrine toxicity by using the MCF-7 tumor as a surrogate estrogen-responsive human organ and to examine the efficacy of TCDD and related Ah receptor-mediated compounds in the management of human estrogen-dependent breast cancer.

Differences in biological activity among batches of lyophilized tice Bacillus Calmette-Guérin and their association with clinical course in Stage I lung cancer.

Various measures of biological activity were studied in batches of lyophilized Tice Bacillus Calmette-Guérin (BCG) that have been used intrapleurally as adjuvant therapy in surgically resected Stage I lung cancer patients by our own group, the North American Lung Cancer Study Group, and the Ludwig Lung Cancer Study Group. The biological activities of BCG that were studied were: (a) inhibition of solid tumor growth in mice following s.c. inoculation of BCG admixed with methylcholanthrene-induced fibrosarcoma cells (MC 43); (b) protection against tumor colonization of lungs and prolongation of survival in mice pretreated intrapleurally with BCG and later inoculated i.v. with a lethal dose of MC 43 tumor cells; and (c) growth properties in vitro, including a determination of the relative amounts of growing and nongrowing material and the sensitivity of growing material to inhibition by isoniazid. Significant differences in biological activity among batches of BCG were found. Some batches of BCG protected mice against circulating tumor cells, while others did not. Batches of BCG which protected mice against circulating tumor cells were found to have greater sensitivity to isoniazid and higher viability than batches which did not elicit this antitumor activity. There were also trends of some batches of BCG outperforming others in the clinic. Cumulative disease-free interval of patients was longer with batches which protected mice against circulating tumor cells than with batches which did not protect mice against circulating tumor cells. The results of this study suggest that preclinical testing of BCG for antitumor activity may improve the efficacy of this agent in future clinical trials.

Purification of alpha-fetoprotein from human cord serum with demonstration of its antiestrogenic activity.

Alpha-fetoprotein (AFP) was purified from pooled human cord serum to determine whether it would be similar to purified mouse AFP in its ability to be transformed into an antiestrogen by incubation with estradiol (E2). Greater purity was attained with a three-step purification procedure of chromatofocusing, Blue-Sepharose chromatography and immunoaffinity chromatography than with a two-step procedure of polyacrylamide gel electrophoresis followed by Blue-Sepharose chromatography. Nevertheless, both procedures rendered AFP in a form that was transformable by E2 to an antiestrogen, although the product of the three-step procedure afforded more consistent biological activity. Removal of albumin from AFP was crucial for transformation of AFP to an antiestrogen. Thus, human AFP is similar to mouse AFP in being transformed to an antiestrogen upon incubation with E2, even though there is only 66% structural homology between the two proteins, and human AFP lacks the high-affinity binding site for E2 present in the mouse AFP molecule.

Alpha-fetoprotein-derived antiestrotrophic octapeptide.

Alpha-fetoprotein (AFP) is a major serum protein produced during fetal development. Experimental findings suggest that AFP has antiestrotrophic activity and that it can be developed as a therapeutic agent to treat existing estrogen-dependent breast cancer or to prevent premalignant foci from developing into breast cancer. The antiestrotrophic activity of AFP was reported to be localized to a peptide consisting of amino acids 447-480, a 34-mer peptide termed P447. A series of parsings and substitutions of amino acids in the P447 sequence was intended to identify the shortest analog which retained antiestrotrophic activity. Peptides related to P447 were generated using solid phase peptide synthesis. Several shorter peptides, including an 8-mer called P472-2 (amino acids 472-479, peptide sequence EMTPVNPG), retained activity, whereas peptides shorter than eight amino acid residues were inactive. The dose-related antiestrotrophic activity of AFP-derived peptides was determined in an immature mouse uterine growth assay that measures their ability to inhibit estradiol-stimulated uterine growth. In this assay, the maximal inhibitory activities exhibited by peptide P472-2 (49%), by peptide P447 (45%), and by intact AFP (35-45%) were comparable. The octapeptide P472-2 was also active against estradiol-stimulated growth of T47D human breast cancer cells in culture. These data suggest that peptide P472-2 is the minimal sequence in AFP, which retains the antiestrotrophic activity found with the full-length molecule. The synthetic nature and defined structure of this 8-mer peptide suggest that it can be developed into a new drug which opposes the action of estrogen, perhaps including the promotional effects of estradiol in the development of human breast cancer.

The recombinant third domain of human alpha-fetoprotein retains the antiestrotrophic activity found in the full-length molecule.

Previous studies have shown that alpha-fetoprotein (AFP) interferes with estrogen (E2)-stimulated growth, including E2-stimulated breast cancer growth. In an effort to localize the antiestrotrophic portion of the molecule, the C-terminal one-third (200 amino acids) of human AFP, known as Domain III, was produced in a baculovirus expression system as a fusion protein containing an amino terminal histidine tag. The histidine tag was included to facilitate purification by metal ion affinity chromatography. The purified recombinant Domain III fusion protein was functionally similar to full-length natural AFP isolated from human cord sera or from cultured human hepatoma cells (HepG2) in that they all produced significant and quantitatively similar inhibition of E2-stimulated growth of immature mouse uterus. Furthermore, the dose-response profiles of the recombinant Domain III AFP and natural full-length AFP were similar. Preincubation of either protein in a molar excess of E2 lowered the minimally effective antiestrotrophic dose and produced a difference spectrum consistent with a change in conformation. These findings indicate that the antiestrotrophic activity of AFP is contained within the third domain of the molecule, and they have obvious implications for the production of biologically active peptides derived from this portion of the AFP molecule.

Alpha-fetoprotein derived from a human hepatoma prevents growth of estrogen-dependent human breast cancer xenografts.

Alpha-fetoprotein (AFP) is a transport protein that has growth-regulatory properties in many different tissues. It is known to interfere with responses stimulated by estrogen. The purpose of this study was to determine whether human AFP would inhibit the growth of human breast cancer. AFP was isolated from the culture supernatant of human hepatoma cells (HepG2) grown in serum-free medium and was purified by immunoaffinity chromatography. Human breast cancers were grown as xenografts under the kidney capsule of severe combined immunodeficient mice. The minimum inhibitory dose of AFP against estradiol (E2)-stimulated growth of human MCF-7 breast cancer xenografts was 10 microg/mouse/day, and maximum inhibition (no growth) was achieved with 100 microg/mouse/day. Daily treatment was required to sustain inhibition. This 100-microg dose of AFP also inhibited xenograft growth of E2-dependent T47 human breast carcinoma. Estrogen receptor-negative MDA MB 231 and BT20 human breast carcinoma xenografts were not inhibited by AFP (100 microg/mouse/day). Elevation in serum E2 occurred during AFP treatment. AFP did not compete with agonists for the estrogen receptor. These laboratory results are consistent with the findings of a literature search, which consistently showed an association between elevated pregnancy levels of AFP and subsequent reduced risk for breast cancer later in life. We conclude that AFP can inhibit growth of estrogen-dependent breast cancer and warrants further development as an agent for the treatment and perhaps even the prevention of human breast cancer.