Decreased expression of BRCA1 accelerates growth and is often present during sporadic breast cancer progression.

We have characterized expression of the familial breast and ovarian cancer gene, BRCA1, in cases of non-hereditary (sporadic) breast cancer and analyzed the effect of antisense inhibition of BRCA1 on the proliferative rate of mammary epithelial cells. BRCA1 mRNA levels are markedly decreased during the transition from carcinoma in situ to invasive cancer. Experimental inhibition of BRCA1 expression with antisense oligonucleotides produced accelerated growth of normal and malignant mammary cells, but had no effect on non-mammary epithelial cells. These studies suggest that BRCA1 may normally serve as a negative regulator of mammary epithelial cell growth whose function is compromised in breast cancer either by direct mutation or alterations in gene expression.

BRCA1 is secreted and exhibits properties of a granin.

Germline mutations in BRCA1 are responsible for most cases of inherited breast and ovarian cancer. However, the function of the BRCA1 protein has remained elusive. We now show that BRCA1 encodes a 190-kD protein with sequence homology and biochemical analogy to the granin protein family. Interestingly, BRCA2 also includes a motif similar to the granin consensus at the C terminus of the protein. Both BRCA1 and the granins localize to secretory vesicles, are secreted by a regulated pathway, are post-translationally glycosylated and are responsive to hormones. As a regulated secretory protein, BRCA1 appears to function by a mechanism not previously described for tumour suppressor gene products.

Overexpression of cyclin D mRNA distinguishes invasive and in situ breast carcinomas from non-malignant lesions.

The elucidation of molecular alterations that occur during human breast cancer progression may contribute to the development of preventative strategies. Using in situ hybridizations on a cohort of 94 biopsy lesions, quantitatively increased cyclin D mRNA expression levels were observed in only 18% of benign lesions, which confer no or slightly increased breast cancer risk, and 18% of premalignant atypical ductal hyperplasias, which confer a four to fivefold increase in breast cancer risk. The transition to carcinoma was accompanied by frequent cyclin D mRNA overexpression in 76% of low-grade ductal carcinomas in situ, 87% of higher grade comedo ductal carcinomas in situ and 83% of infiltrating ductal breast carcinomas. The data identify a molecular event that may separate benign and premalignant human breast lesions from any form of breast carcinoma.

Temporal multispectral and 3D analysis of Cerro de Pasco, Peru.

Mining operations across the world often lead to contamination of land, water resources, ecosystems and in some cases, entire communities.Results of recent health and ground sampling studies revealed extensive lead contamination within the populace and around the City of Cerro de Pasco, Peru. Tailings excavated from a large open pit zinc mine in the center of the city have been aggregated in four large stockpiles within close proximity to neighborhoods, schools, and hospitals. Visual comparison of ASTER (Advanced Spaceborne Thermal Emission and Reflection Radiometer) imagery from 2001 and Sentinel-2 imagery from 2018 suggests a size increase in one tailing stockpile in particular near the neighborhood of Paragsha. Due to ongoing mining efforts, the hypothesis motivating the work presented here is that Pb-bearing minerals would be detectable through multispectral analysis, an increase in Pb mineral percent abundance would be observed and tailing stockpile volume would be detectable between 2001 and 2016. This hypothesis is tested using Spectral Angle Mapper (SAM), Adaptive Coherence Estimator (ACE), and Jeffries-Matusita distance calculation on ASTER (2001) and Sentinel-2 (2018) VNIR and SWIR bands. Volume and area estimate of tailing stockpiles were calculated using a photogrammetrically derived point cloud. SAM detected the presence of five Pb-bearing minerals around Cerro de Pasco and Paragsha. The results of the temporal SAM analysis displayed an increase of approximately 17% of Pb-bearing minerals around the greater Cerro de Pasco city area and approximately 11% for the neighborhood of Paragsha. Jeffries-Matusita distance results suggest clear correlation between contamination sources and affected locations. Total tailing stockpile volume was measured to be approximately 200,300,000 m3. Volume for Pile 4 was estimated to have increased by approximately 46,000,000 m3 between 2001 and 2018. These presented results will hopefully inspire and guide future remote sensing campaigns, perhaps involving a UAV or aircraft-based hyperspectral instrument.

Creation of "amyloid" fibrils from Bence Jones proteins in vitro.

"Amyloid" fibrils have been created from some human Bence Jones proteins by proteolytic digestion under physiologic conditions. These fibrils with an antiparallel, beta-pleated sheet conformation consist of only a portion of the variable region of the immunoglobulin light polypeptide chain and share the physical properties of amyloid fibrils. The relation between amyloidosis and immunoglobulins is thus more firmly established and a pathogenetic mechanism for amyloid fibril formation is suggested.

Multicenter study to assess potential hazards from exposure to lipid peroxidation products in soya bean oil from Trilucent breast implants.

In response to a Hazard Notice by the Medical Devices Agency of the UK in 2000 regarding the Trilucent breast implant (TBI), an expert panel was convened to implement a research program to determine whether genotoxic compounds were formed in the soybean oil filler (SOF) of TBIs and whether these could be released to produce local or systemic genotoxicity. The panel established a research program involving six laboratories. The program recruited 47 patients who had received TBIs (9 patients had received silicone implants previously). A reference group (REBI) of 34 patients who had exchanged either silicone (17 patients) implants (REBI-E) or patients (17) who were to receive primary implantation augmentation with silicone (REBI-PIA), and who were included as needed to increase either the pre- or post-explantation sample number. Of the 17 REBI-E patients, 5 had silicone implants and 12 had saline implants previously (prior to the last exchange). Investigation was undertaken before and after replacement surgery in the TBI patients and before and after replacement or augmentation surgery in the REBI patients. The pre- to post-operative sample interval was 8-12 weeks. Pre-operative samples were collected within 7 days prior to the operation. Information on a variety of demographic and behavioral features was collected. Biochemical and biological endpoints relating to genotoxic lipid peroxidation (LPO) products potentially formed in the SOF, and released locally or distributed systemically, were measured. The SOF of explanted TBIs was found to have substantial levels of LPO products, particularly malondialdehyde (MDA), and low levels of trans-4-hydroxy-2-nonenal (HNE) not found in unused implants. Mutagenicity of the SOF was related to the levels of MDA. Capsules that formed around TBIs were microscopically similar to those of reference implants, but MDA-DNA adducts were observed in capsular macrophages and fibroblasts of only TBI capsules. These cell types are not progenitors of breast carcinoma (BCa) and the location of the implants precludes LPO products reaching the mammary epithelial cells which are progenitors of BCa. Blood levels of LPO products were not increased in TBI patients compared to REBI patients and did not change with explantation. In TBI patients, white blood cells did not show evidence of increased levels of LPO-related aldehyde DNA adducts. In conclusion, based on a number of measured parameters, there was no evident effect that would contribute to breast or systemic cancer risk in the TBI patients, and the recommended treatment of TBI patients involving explantation was judged appropriate.

Modification of chemically induced diabetes in rats by vitamin E. Supplementation minimizes and depletion enhances development of diabetes.

Administration of the antioxidant vitamin E to rats, prior to administration of either streptozotocin or alloxan, provided protection against the diabetogenic effect of both these agents. This was demonstrated by their response to a glucose load, their pancreatic insulin content and light microscopy findings. In addition, rats whose antioxidant state was depleted, by being maintained on a vitamin E and selenium-deficient diet, demonstrated increased diabetogenic susceptibility to normally nondiabetogenic doses of streptozotocin. These findings provide indirect support for the suggestion that the chemical agents streptozotocin and alloxan may exert their diabetogenic effect by acting as oxidants or free radical producers.

Structural identity of Bence Jones and amyloid fibril proteins in a patient with plasma cell dyscrasia and amyloidosis.

The partial amino acid sequence of the amyloid fibril protein isolated from the small intestine of a patient with plasma cell dyscrasia and associated amyloidosis has been determined and compared with the sequence of the kappa-type Bence Jones protein isolated from the urine of the same patient. Identical sequences were observed for the 27 amino-terminal residues that could be compared. The C-terminal tryptic peptide of the amyloid protein was identical with that of the Bence Jones protein. Apparent molecular weights and amino acid compositions of the Bence Jones and amyloid proteins were similar. It appears, therefore, that the predominant protein present in the amyloid deposits in this patient was an intact kappa-type light polypeptide chain that was identical with the urinary Bence Jones protein.

Expression of tumor-associated antigen (DF3) in atypical hyperplasias and in situ carcinomas of the human breast.

The monoclonal antibody (MoAb) DF3 prepared against a membrane-enriched fraction of human breast carcinoma has previously shown a differential reactivity to cytoplasmic antigen in carcinomas versus antigen concentrated on apical borders in benign lesions of the breast. In the present report the cytoplasmic reactivity of MoAb DF3 within a spectrum of benign and malignant breast lesions was studied to define whether the DF3 antigen is expressed in the cytoplasm of potentially premalignant lesions, i.e., atypical hyperplasias, or early malignant lesions, i.e., in situ carcinomas. Biopsy specimens of breast lesions from 108 women, including 28 patients with invasive carcinoma, 12 with in situ carcinoma, 17 with atypical hyperplasia, 25 with proliferative lesions without atypia, and 26 with nonproliferative lesions, were examined for DF3 antigen expression with the use of an indirect immunohistochemical method. Atypical hyperplasias were less reactive with MoAb DF3 than invasive carcinomas (P = .05 by Wilcoxon rank sum test). No significant statistical differences were observed, however, between invasive carcinomas and in situ carcinomas or between in situ carcinomas and atypical hyperplasias on the basis of cytoplasmic DF3 reactivity. Invasive carcinomas, in situ carcinomas, and atypical hyperplasias, however, demonstrated significantly higher reactivity with MoAb DF3 in the cytoplasm than proliferative lesions without atypia and nonproliferative lesions (P less than .01). These studies demonstrate that atypical hyperplasias express elevated levels of a given tumor-associated antigen and thus provide further immunologic evidence that these lesions are premalignant.

Pathogenesis of Paget's disease: epidermal heregulin-alpha, motility factor, and the HER receptor family.

BACKGROUND AND METHODS: In Paget's disease of the breast, the epidermis of the nipple is infiltrated by large neoplastic cells of glandular origin. It has been hypothesized that the spread of Paget cells through the nipple epidermis is induced by a motility factor that acts via the HER2/NEU receptor. To test this hypothesis, we characterized and purified a motility factor released by keratinocytes and identified its target receptors in specimens from patients with Paget's disease and in SK-BR-3 breast adenocarcinoma cells, which overexpress HER2/NEU. RESULTS: We isolated the motility factor from keratinocyte-conditioned medium and sequenced tryptic peptides. These sequences were used to identify the motility factor as heregulin-alpha, which is released by skin keratinocytes. Heregulin-alpha induces spreading, motility, and chemotaxis of SK-BR-3 cells, as does motility factor. Motility factor activities of heregulin-alpha are inhibited by monoclonal antibody AB2, directed against the extracellular domain of HER2/NEU, which blocks the binding of heregulin-alpha. We used in situ hybridization to show that normal epidermal cells produce heregulin-alpha messenger RNA and that heregulin receptors, HER3 and/or HER4, as well as their coreceptor HER2/NEU, are expressed by Paget cells. CONCLUSIONS: Heregulin-alpha is a motility factor that is produced and released by normal epidermal keratinocytes and thus plays a key role in the pathogenesis of Paget's disease. Paget cells express heregulin receptors HER2/NEU, as well as HER3 and/or HER4, both of which function as a co-receptor of HER2/NEU. Binding of heregulin-alpha to the receptor complex on Paget cells results in the chemotaxis of these breast cancer cells, which eventually migrate into the overlying nipple epidermis.

Transforming growth factor-beta and breast cancer risk in women with mammary epithelial hyperplasia.

BACKGROUND: Transforming growth factors-beta (TGF-betas) regulate mammary epithelial cell division. Loss of expression of TGF-beta receptor II (TGF-beta-RII) is related to cell proliferation and tumor progression. Breast epithelial hyperplastic lesions lacking atypia (EHLA) are associated with a mild elevation in breast cancer risk. We investigated the expression of TGF-beta-RII in EHLA and the risk of subsequent invasive breast cancer. METHODS: We conducted a nested case-control study of women with biopsy-confirmed EHLA who did not have a history of breast cancer or atypical hyperplasia of the breast. Case patients (n = 54) who subsequently developed invasive breast cancer were matched with control patients (n = 115) who did not. Formalin-fixed, paraffin-embedded sections of breast biopsy specimens of all 169 patients with EHLA were studied by immunohistochemical analysis with antibodies against TGF-beta-RII. All P values are two-sided. RESULTS: Women with breast EHLA and 25%-75% TGF-beta-RII-positive cells or less than 25% TGF-beta-RII-positive cells had odds ratios of invasive breast cancer of 1.98 (95% confidence interval [CI] = 0.95-4.1) or 3.41 (95% CI = 1.2-10.0), respectively (P for trend =.008). These risks are calculated with respect to women with EHLA that had greater than 75% TGF-beta-RII expression. Women with a heterogeneous pattern of TGF-beta-RII expression in their normal breast lobular units and either greater than 75%, 25%-75%, or less than 25% positive cells in their EHLA had odds ratios for breast cancer risk of 0.742 (95% CI = 0.3-1.8), 2.85 (95% CI = 1.1-7.1), or 3.55 (95% CI = 1.0-10.0), respectively (P for trend =.003). These risks are relative to women with a homogeneous pattern of expression in their normal lobular units and greater than 75% positive cells in their EHLA. CONCLUSION: This study indicates that loss of TGF-beta-RII expression in epithelial cells of EHLA is associated with increased risk of invasive breast cancer.

Relation between component parts of fibrocystic disease complex and breast cancer.

Specimens of benign breast disease obtained from biopsies performed at Vanderbilt Hospital (Nashville, Tenn.) between 1952 and 1959 were histologically reviewed and characterized as to individual component types of fibrocystic disease. Follow-up for information regarding breast cancer development was 94% successful. Carcinoma developed more often when epithelial proliferative lesions were present. Atypical lobular hyperplasia had a greater predictive value than other epithelial lesions and was associated with an elevated risk six times that expected prior to the age of 45 years and a tripling of risk after the age of 45 years. Various ductal hyperplastic lesions are associated with approximately a doubly increased risk that is present only if the lesions are identified at biopsy after the age of 45 years. Women with cysts, sclerosing adenosis, fibrosis, and other nonhyperplastic changes were at no greater risk for subsequent carcinoma than women in the general population.

Ductal lavage for detection of cellular atypia in women at high risk for breast cancer.

BACKGROUND: Breast cancer originates in breast epithelium and is associated with progressive molecular and morphologic changes. Women with atypical breast ductal epithelial cells have an increased relative risk of breast cancer. In this study, ductal lavage, a new procedure for collecting ductal cells with a microcatheter, was compared with nipple aspiration with regard to safety, tolerability, and the ability to detect abnormal breast epithelial cells. METHODS: Women at high risk for breast cancer who had nonsuspicious mammograms and clinical breast examinations underwent nipple aspiration followed by lavage of fluid-yielding ducts. All statistical tests were two-sided. RESULTS: The 507 women enrolled included 291 (57%) with a history of breast cancer and 199 (39%) with a 5-year Gail risk for breast cancer of 1.7% or more. Nipple aspirate fluid (NAF) samples were evaluated cytologically for 417 women, and ductal lavage samples were evaluated for 383 women. Adequate samples for diagnosis were collected from 111 (27%) and 299 (78%) women, respectively. A median of 13,500 epithelial cells per duct (range, 43-492,000 cells) was collected by ductal lavage compared with a median of 120 epithelial cells per breast (range, 10-74,300) collected by nipple aspiration. For ductal lavage, 92 (24%) subjects had abnormal cells that were mildly (17%) or markedly (6%) atypical or malignant (<1%). For NAF, corresponding percentages were 6%, 3%, and fewer than 1%. Ductal lavage detected abnormal intraductal breast cells 3.2 times more often than nipple aspiration (79 versus 25 breasts; McNemar's test, P<.001). No serious procedure-related adverse events were reported. CONCLUSIONS: Large numbers of ductal cells can be collected by ductal lavage to detect atypical cellular changes within the breast. Ductal lavage is a safe and well-tolerated procedure and is a more sensitive method of detecting cellular atypia than nipple aspiration.

Tumor-associated chromatin antigens of human colon adenocarcinoma cell lines HT-29 and LoVo.

Antiserum to dehistonized chromatin from human colon adenocarcinoma cell line HT-29 was raised in rabbits and used for the immunodetection of colon tumor-associated nuclear antigens. Quantitative microcomplement-fixation studies indicated that the antiserum had reactivity similar to those of chromatins of two human colon adenocarcinoma cell lines (HT-29 and LoVo) and with nonneoplastic colon. Immunocytochemical localization showed the chromatin antigens to be evenly dispersed throughout the nucleus. Immunochemical staining of electrophoretically separated chromosomal proteins transferred to nitrocellulose sheets revealed several intensely staining antigens predominantly in the molecular weight range of 62,000 to 75,000. When the antiserum was immunoabsorbed with nonneoplastic human colon chromatin, two antigens with molecular weights of 67,000 and 92,000 were identified only with the tumor chromatins. Antiserum immunoabsorbed with either LoVo or HT-29 chromatin failed to show any immunoreactivity, suggesting that these tumor-associated proteins, or antigenic sites residing on these proteins, are identical in both colon tumor cell lines.

Antigenic changes in nonhistone proteins during azo dye hepatocarcinogenesis.

We have investigated the appearance of specific nonhistone proteins during azo dye-induced hepatocarcinogenesis in the rat. Groups of animals fed azo dye-containing diet were sacrificed at approximately 3-week intervals, portions of their livers were examined histologically, and the remaining material was fractionated into chromatin and cytoplasmic fractions. Livers of the azo dye-fed animals exhibited histological changes that have been classically attributed to the course and development of cancer; by 28 to 30 weeks of treatment, nearly all animals had developed hepatomas. Heterogeneous rabbit antisera were prepared to dehistonized chromatin from several azo dye-induced hepatomas. These antisera were then used to assess various chromatins for the appearance of antigens specific for neoplasia during inducing carcinogenesis using immunodetection of antigens separated electrophoretically and transferred to nitrocellulose. Changes in the immunoreactivity of liver chromosomal proteins during carcinogen treatment were evident after 3 weeks, and the antigenic profiles of various chromatin samples gradually assumed the characteristics of the hepatoma. The transformation was accompanied by qualitative changes in chromosomal protein antigens, and although these antigenic species were not directly quantitated, noticeable enrichment of tumor-specific species occurred with treatment time. Immunotransfer assays of cytoplasmic fractions indicated most antigens to be specific for chromatin. Normal tissue chromatin exhibited minimal immunoreactivity, and slightly more antigenic homology was noted with regenerating liver and most transplantable tumor chromatins. Interestingly, the transplantable tumor Walker 256 carcinosarcoma was highly enriched in antigens recognized by antisera to azo dye hepatoma dehistonized chromatin. These studies establish a define chronological correlation between the chemical induction of cancer and sequential changes in the immunological specificity of nonhistone protein antigens.

Expression of the 21,000 molecular weight ras protein in a spectrum of benign and malignant human mammary tissues.

Monoclonal antibodies RAP-5 and Y13-259, directed against the ras gene product [a protein with a molecular weight of 21,000 (p21)] have been used to evaluate ras p21 expression in malignant and benign mammary tissues as well as in the lesions of intermediate stature such as atypical hyperplasia using immunohistochemical assays. Invasive carcinoma demonstrated enhanced expression of ras p21, with generally decreasing expression in carcinoma in situ, atypical hyperplasia, and nonatypical hyperplasia, respectively. Heterogeneous expression of ras p21 was observed among primary as well as metastatic mammary carcinomas. Carcinomas from postmenopausal patients generally demonstrated higher levels of ras p21 than those from premenopausal patients, but no significant difference in ras p21 expression in carcinomas between estrogen-receptor rich and estrogen-receptor poor patients was found. Normal mammary epithelium in terminal duct lobular units from patients with hyperplasia generally demonstrated higher levels of ras p21 expression than did epithelium in large ducts. This demonstration of enhanced ras p21 expression by the epithelium of peripheral lobular portion of the breast is consistent with the previous hypothesis that these areas preferentially undergo malignant transformation. Analyses of the limited number of specimens available from patients with 15-yr follow-up revealed a generally higher level of ras p21 in hyperplasia from patients who subsequently developed carcinoma, as compared to those from patients without carcinoma development. However, no conclusions regarding the potential for malignant transformation could be drawn for any individual patient on the basis of ras p21 expression. Concomitant analyses of ras p21 expression in mammary carcinomas and benign lesions using liquid competition radioimmunoassay and immunohistochemical assay demonstrated the complementary nature of these alternative approaches. These results suggest that enhanced ras p21 expression may be involved in the early stages of mammary carcinogenesis but is probably not involved in the maintenance of the transformed phenotype.

Characterization of monoclonal antibodies to novikoff hepatoma cytokeratin antigen p39.

Three stable monoclonal antibody-producing mouse hybridoma lines have been developed which produce high-titer, immunoglobulin M antibodies specific for the Novikoff ascites hepatoma (NAH) Mr 39,000 cytokeratin antigen (p39). Immunotransfer assays of cytoskeletal protein-enriched fractions indicated p39 to be present in a range of rat tissues, including colon, breast, lung, and uterus. Two-dimensional gel immunoblots confirmed that immunoreactivity in the latter tissues was for polypeptides with similar isoelectric points to those of NAH p39; however, reactivity in the colon contained a wide range of additional isomeric forms. Immunohistochemical localization studies with these antibodies revealed enrichment of p39 in the simple epithelia or ductular structures of organs containing this antigen. In all sections examined, glandular epithelia were observed to be only weakly immunoreactive. Additional immunoblot and immunocytochemical analyses with the monoclonal antibodies and polyspecific antisera to NAH cytokeratin suggest the human Mr 40,000 cytokeratin to be similar to but not identical to NAH p39.

Isolation of completely inactive plasma prorenin and its activation by kallikreins. A possible new link between renin and kallikrein.

Existing views on prorenin are conflicting and its physiological activation mechanism is not clear. In an attempt to obtain clearcut views on the molecular properties of prorenin in human plasma, the renin zymogen (prorenin) was separated from active renin by two steps of affinity chromatography and it was demonstrated that prorenin is a completely inactivate zymogen contrary to the existing information. Inactive prorenin has an apparent molecular of 56,000 contrary to 46,000-43,000 of partially active prorenin. Isolated and acid-treated human prorenin was shown to be activated by kallikreins from human urine and plasma. This activation was completely blocked by Trasylol. Hog pancreatic kallikrein also activated human prorenin. The kallikrein mediated activation of prorenin indicates the existence of a new link between the vasoconstricting renin-angiotensin system and the vasodilating kallikreinkinin system.

Prognostic value of histologic grade and proliferative activity in axillary node-positive breast cancer: results from the Eastern Cooperative Oncology Group Companion Study, EST 4189.

PURPOSE: The identification of a subset of patients with axillary lymph node-positive breast cancer with an improved prognosis would be clinically useful. We report the prognostic importance of histologic grading and proliferative activity in a cohort of patients with axillary lymph node-positive breast cancer and compare these parameters with other established prognostic factors. PATIENTS AND METHODS: This Eastern Cooperative Oncology Group laboratory companion study (E4189) centered on 560 axillary lymph node-positive patients registered onto one of six eligible clinical protocols. Flow cytometric (ploidy and S-phase fraction [SPF]) and histopathologic analyses (Nottingham Combined Histologic Grade and mitotic index) were performed on paraffin-embedded tissue from 368 patients. RESULTS: Disease recurred in 208 patients; in 161 (77%), within the first 5 years. Mitotic index and grade were associated with both ploidy and SPF (P

Treatment with farnesyl-protein transferase inhibitor induces regression of mammary tumors in transforming growth factor (TGF) alpha and TGF alpha/neu transgenic mice by inhibition of mitogenic activity and induction of apoptosis.

Mouse mammary tumor virus-transforming growth factor alpha (MMTV-TGF alpha) and MMTV-TGF alpha/neu transgenic mice develop mammary tumors after a long latency and therefore provide useful model systems for breast cancer with its recognized activation of receptor tyrosine kinase signaling. We used these mice to study the antitumor effect of L-744,832 (FTI), a potent and selective inhibitor of farnesyl-protein transferase, and hence of Ras function. A total of 55 mice were assigned randomly to treatment with FTI or vehicle, and one-half of the mice were crossed over after initial treatment to the opposite group. L-744,832 induced reversible regression of mammary tumors that was paralleled by a decrease in serum levels of TGF alpha secreted by the tumor cells. There was no difference in response to treatment with FTI between MMTV-TGF alpha mice, in which tumorigenesis was accelerated by multiparity or the chemical carcinogen 7,12-dimethylbenzanthracene, and MMTV-TGF alpha/neu mice. The tumor histological type had no impact on FTI sensitivity. For mechanistic analyses, tumor excision biopsies were obtained from 12 mice before and after treatment with L-744,832. In these samples, tumor regression was paralleled biochemically by inhibition of mitogen-activated protein kinase activity and biologically by an increase in G1-phase and decrease in S-phase fractions, as well as induction of apoptosis. These results suggest that the potential clinical use of FTI could be expanded to include cancers harboring activated receptor tyrosine kinases as well as those containing activated Ras.