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David E Wazer

Publications and source records attributed to David E Wazer.

36 records · Page 2Linked to original sources
PubMed2004

A comparison of the expected costs of high dose rate brachytherapy using 252Cf versus 192Ir.

A cost analysis to compare high dose rate (HDR) brachytherapy using either californium-252 (252Cf) or 192Ir was performed to determine the prospects of widespread clinical implementation of HDR 252Cf. Interest in the neutron-emitting 252Cf radioisotope as a radiotherapy nuclide has undergone a resurgence given recent efforts to fabricate HDR remotely afterloaded sources, and other efforts to create a miniature source for improved accessibility to a variety of anatomic sites. Therefore, HDR 252Cf brachytherapy may prove to be a potential rival to the use of HDR 192Ir remotely afterloaded brachytherapy--the current standard-of-care treatment modality using HDR brachytherapy. Considering the possible improvements in clinical efficacy using HDR 252Cf brachytherapy and the enormous costs of other high-LET radiation sources, the cost differences between 252Cf and 192Ir may be well-justified.

Brachytherapy↗
PubMed2003

Loss of expression of the putative tumor suppressor NES1 gene in biopsy-proven ductal carcinoma in situ predicts for invasive carcinoma at definitive surgery.

PURPOSE: The loss of expression of NES1, a novel putative tumor suppressor gene, is an early marker of breast tumorigenesis. NES1 is expressed in normal breast tissue and ductal hyperplasia but is absent or markedly diminished in invasive cancer. In cases of ductal carcinoma in situ (DCIS), NES1 expression has been shown previously to be present in approximately 50% of specimens. This study examined the expression level of NES1 in diagnostic biopsy samples found to contain pure DCIS. These data were then correlated with the pathologic findings found at definitive local surgery. METHODS AND MATERIALS: Twenty-nine cases with initial biopsy showing DCIS without invasive carcinoma followed by subsequent reexcision were discovered and archived. Formalin-fixed tissue specimens were obtained for analysis. Each biopsy specimen was subjected to hematoxylin-eosin staining and reviewed by two pathologists to confirm the diagnosis of pure DCIS. NES1 cDNA (1069 bp), including 238 bp of 5' and 3' untranslated region and the entire protein-coding region, was cloned into a vector. To generate the antisense and sense RNA probes, the plasmid was linearized and the transcription reaction was carried out with polymerases T7 and T3, respectively. The detection of in situ hybridization probes was performed using an mRNAlocator-Biotin Kit. Staining was characterized as negative (0/1+) or positive (2+/3+). Subsequent to an initial biopsy diagnosis of DCIS, all cases had a definitive surgical procedure. Detailed sectioning of the resultant tissue was performed and subjected to hematoxylin-eosin staining to determine the presence or absence of invasive carcinoma. RESULTS: The initial diagnostic biopsy specimens showed that 17 of 17 high-grade, 3 of 7 intermediate-grade, and 3 of 5 low-grade DCIS specimens were negative for NES1 expression. Of the 6 cases of DCIS found to be positive for NES1 expression, none (0%) were subsequently found to have invasive carcinoma at definitive surgery. In contrast, the loss of NES1 expression in the initial diagnostic biopsy was associated with a 40% incidence of invasive carcinoma at definitive surgery. Additional stratification by nuclear grade showed invasive carcinoma in 5 (83%) of 6 NES1-negative, low- to intermediate-grade DCIS (p </=0.01) and 4 (24%) of 17 NES1-negative, high-grade DCIS (p </=0.05). CONCLUSION: These results show that a lack of NES1 expression in DCIS identified at the diagnostic biopsy predicts for a high risk of invasive cancer in the definitive surgical specimen. The predictive value of NES1 expression appears to be particularly relevant for low- and intermediate-grade DCIS.

Adult↗
PubMed2003

Conservative management of Paget disease of the breast with radiotherapy: 10- and 15-year results.

BACKGROUND: At 5-year follow-up, patients with Paget disease of the breast who were treated with breast-conserving surgery (BCS) and radiotherapy (RT) had excellent results. The current report provides 10- and 15-year rates of tumor control in the breast, as well as disease-free and overall survival rates following BCS and RT in a cohort of patients with Paget disease presenting without a palpable mass or mammographic density. METHODS: Through a collaborative review of patients treated with BCS and RT from seven institutions, 38 cases of Paget disease of the breast presenting without a palpable mass or mammographic density were identified. All patients had pathologic confirmation of typical Paget cells at time of diagnosis. Thirty-six of 38 patients had a minimum follow-up greater than 12 months and constitute the study cohort. Ninety-four percent of patients underwent complete or partial excision of the nipple-areola complex and all patients received a median external beam irradiation dose of 50 Gy (range, 45-54 Gy) to the whole breast. Ninety-seven percent of patients also received a boost to the remaining nipple or tumor bed, a median total dose of 61.5 Gy (range, 50.4-70 Gy). RESULTS: With median follow-up of 113 months (range, 18-257 months), 4 of 36 patients (11%) developed a first recurrence of disease in the treated breast only. Two of the four recurrences in the breast were ductal carcinoma in situ (DCIS) only and two were invasive with DCIS. Two additional patients had a recurrence in the breast as a component of first failure. Actuarial local control rates for the breast as the only site of first recurrence were 91% at 5 years (95% confidence interval [CI], 80-100%) and 87% (95% CI, 75-99%) at both 10 and 15 years. Actuarial local control rates for breast recurrence, as a component of first failure, were 91% (95% CI, 80-100%), 83% (95% CI, 69-97%), and 76% (95% CI, 58-94%) at 5, 10, and 15 years, respectively. No clinical factors were identified as significant predictors for breast recurrence. Five-, 10- and 15-year actuarial rates for survival without disease of 97% (95% CI, 90-100%) and 5-, 10-, and 15-year actuarial rates of overall survival of 93% (95% CI, 84-100%) at 5 years and 90% (95% CI, 78-100%) at 10 and 15 years were reported. CONCLUSIONS: These data confirm excellent rates of local control, disease-free survival, and overall survival at 10 and 15 years following BCS and RT for Paget disease of the breast. This study continues to support the recommendation of local excision and definitive breast irradiation as an alternative to mastectomy in the treatment of patients with Paget disease presenting without a palpable mass or mammographic density.

Adult↗
PubMed2003

ErbB2 degradation mediated by the co-chaperone protein CHIP.

ErbB2 overexpression contributes to the evolution of a substantial group of human cancers and signifies a poor clinical prognosis. Thus, down-regulation of ErbB2 signaling has emerged as a new anti-cancer strategy. Ubiquitinylation, mediated by the Cbl family of ubiquitin ligases, has emerged as a physiological mechanism of ErbB receptor down-regulation, and this mechanism appears to contribute to ErbB2 down-regulation induced by therapeutic anti-ErbB2 antibodies. Hsp90 inhibitory ansamycin antibiotics such as geldanamycin (GA) induce rapid ubiquitinylation and down-regulation of ErbB2. However, the ubiquitin ligase(s) involved has not been identified. Here, we show that ErbB2 serves as an in vitro substrate for the Hsp70/Hsp90-associated U-box ubiquitin ligase CHIP. Overexpression of wild type CHIP, but not its U-box mutant H260Q, induced ubiquitinylation and reduction in both cell surface and total levels of ectopically expressed or endogenous ErbB2 in vivo, and this effect was additive with that of 17-allylamino-geldanamycin (17-AAG). The CHIP U-box mutant H260Q reduced 17-AAG-induced ErbB2 ubiquitinylation. Wild type ErbB2 and a mutant incapable of association with Cbl (ErbB2 Y1112F) were equally sensitive to CHIP and 17-AAG, implying that Cbl does not play a major role in geldanamycin-induced ErbB2 down-regulation. Both endogenous and ectopically expressed CHIP and ErbB2 coimmunoprecipitated with each other, and this association was enhanced by 17-AAG. Notably, CHIP H260Q induced a dramatic elevation of ErbB2 association with Hsp70 and prevented the 17-AAG-induced dissociation of Hsp90. Our results demonstrate that ErbB2 is a target of CHIP ubiquitin ligase activity and suggest a role for CHIP E3 activity in controlling both the association of Hsp70/Hsp90 chaperones with ErbB2 and the down-regulation of ErbB2 induced by inhibitors of Hsp90.

Benzoquinones↗
PubMed2003

Long-term follow-up of a prospective policy of margin-directed radiation dose escalation in breast-conserving therapy.

BACKGROUND: A prospectively applied treatment policy for breast-conserving therapy used margin assessment as the exclusive guide to the intensity of radiation therapy directed at the tumor bed. METHODS: From 1982 to 1994, 498 women with 509 Stage I/II breast carcinomas with a median follow-up of 121 months were treated. Final margin status (FMS) categories were defined as greater than 5 mm, greater than 2-5 mm, greater than 0-2 mm, and positive. For margins less than or equal to 2 mm or indeterminate, reexcisions were performed if feasible. All patients received whole breast irradiation to 50.0-50.4 Gy. Final tumor bed boosts as a function of FMS were as follows: no residual on reexcision, no boost performed; FMS greater than 5 mm, boost of 10 Gy; FMS greater than 2-5 mm, boost of 14 Gy; FMS greater than 0-2 mm or positive, boost of 20 Gy. Cases were analyzed for local failure with respect to histology, age, tumor size, excision volume, reexcision, and total dose. RESULTS: FMS was positive, greater than 0-2 mm, greater than 2-5 mm, and greater than 5 mm, and no residual tumor on reexcision in 21%, 20%, 17%, 14%, and 28% of cases, respectively. At 12 years, Kaplan-Meier local failure rates were 17% for FMS positive, 9% for FMS greater than 0-2 mm, 5% for FMS greater than 2-5 mm, 0% for FMS greater than 5 mm, and 6% for specimens without evidence of residuum on reexcision (P = 0.009). Patients 45 years old and younger had a 12-year local failure rate of 15% whereas patients older than 45 years had a 12-year local failure rate of 6% (P = 0.01). On multivariate analysis, young age (P = 0.03) predicted increased local failure rate, whereas margins that were less than or equal to 2 mm or positive predicted late (> 5 years) but not early (< or = 5 years) recurrence (P = 0.003). CONCLUSIONS: Graded tumor bed dose escalation in response to FMS results in very low rates of local failure over the first 5 years for all FMS categories. However, tumors with close/positive margins have significantly increased local failure rates after 5 years of follow-up even with increased radiation boost dose. In addition, graded tumor bed dose escalation does not fully overcome the adverse influence of young age.

Adult↗
PubMed2003

Accelerated partial breast irradiation: an updated report from the American Brachytherapy Society.

Logistical barriers of time and travel created by the conventional six-week course of radiotherapy prevent many women from pursuing breast conservation treatment. For the past 12 years, Accelerated Partial Breast Irradiation (APBI) has been investigated as a potential alternative treatment approach in women with early stage breast cancer. The ability to complete treatment in five days has the potential to provide additional women with the option of breast conservation. The validity of this APBI is supported in the study of in-breast recurrence patterns, pathologic data and the clinical treatment experience. The review of the recent data on contemporary APBI reveals that patient selection criteria and brachytherapy quality assurance are clearly critical components and necessary to assure a successful treatment outcome. This updated report from the American Brachytherapy Society on Accelerated Partial Breast Irradiation reviews the appropriate background data supporting this treatment approach with conclusions regarding patient selection criteria and treatment delivery.

Advisory Committees↗
PubMed2003

Determination of the 4 mm Gamma Knife helmet relative output factor using a variety of detectors.

Though the 4 mm Gamma Knife helmet is used routinely, there is disagreement in the Gamma Knife users community on the value of the 4 mm helmet relative output factor. A range of relative output factors is used, and this variation may impair observations of dose response and optimization of prescribed dose. To study this variation, measurements were performed using the following radiation detectors: silicon diode, diamond detector, radiographic film, radiochromic film, and TLD cubes. To facilitate positioning of the silicon diode and diamond detector, a three-dimensional translation micrometer was used to iteratively determine the position of maximum detector response. Positioning of the films and TLDs was accomplished by manufacturing custom holders for each technique. Results from all five measurement techniques indicate that the 4 mm helmet relative output factor is 0.868 +/- 0.014. Within the experimental uncertainties, this value is in good agreement with results obtained by other investigators using diverse techniques.

Radiometry↗
PubMed2003

The high-risk human papillomavirus type 16 E6 counters the GAP function of E6TP1 toward small Rap G proteins.

We have recently identified E6TP1 (E6-targeted protein 1) as a novel high-risk human papillomavirus type 16 (HPV16) E6-binding protein. Importantly, mutational analysis of E6 revealed a strong correlation between the transforming activity and its abilities to bind and target E6TP1 for ubiquitin-mediated degradation. As a region within E6TP1 has high homology with GAP domains of known and putative Rap GTPase-activating proteins (GAPs), these results raised the possibility that HPV E6 may alter the Rap small-G-protein signaling pathway. Using two different approaches, we now demonstrate that human E6TP1 exhibits GAP activity for Rap1 and Rap2, confirming recent findings that a closely related rat homologue exhibits Rap-specific GAP activity. Using mutational analysis, we localize the GAP activity to residues 240 to 945 of E6TP1. Significantly, we demonstrate that coexpression of HPV16 E6, by promoting the degradation of E6TP1, enhances the GTP loading of Rap. These results support a role of Rap small-G-protein pathway in E6-mediated oncogenesis.

Cell Line↗
PubMed2002

The Bmi-1 oncogene induces telomerase activity and immortalizes human mammary epithelial cells.

The vast majority of breast cancers are carcinomas that arise from mammary epithelial cells (MECs). One of the key early events in tumorigenic transformation is the ability of cells to overcome replicative senescence. However, the precise genetic changes that are responsible for this event in MECs is largely unknown. Here, we report that Bmi-1, originally identified as a c-Myc cooperating oncoprotein, can bypass senescence, extend the replicative life span, and immortalize MECs. Furthermore, Bmi-1 was overexpressed in immortal MECs and several breast cancer cell lines. Overexpression of Bmi-1 in MECs led to activation of human telomerase reverse transcriptase (hTERT) transcription and induction of telomerase activity. Telomerase induction by Bmi-1 was an early event in the extension of the replicative life span and immortalization. Bmi-1 was not overexpressed in hTERT-immortalized MECs, suggesting that Bmi-1 functions upstream of hTERT. Although, c-Myc has been reported to induce telomerase in MECs, Bmi-1 appeared to act independently of c-Myc binding sequences in the hTERT promoter. Deletion analysis of the Bmi-1 protein suggested that the RING finger, as well as a conserved helix-turn-helix-turn domain, were required for its ability to induce telomerase and immortalize MECs. These data suggest that Bmi-1 regulates telomerase expression in MECs and plays a role in the development of human breast cancer.

Binding Sites↗
PubMed2002

Implementation and utility of a daily ultrasound-based localization system with intensity-modulated radiotherapy for prostate cancer.

PURPOSE: To evaluate the clinical feasibility of daily computer-assisted transabdominal ultrasonography for target position verification in the setting of intensity-modulated radiotherapy (IMRT) for prostate cancer. METHODS AND MATERIALS: Twenty-three patients with clinically localized prostate cancer were treated using a sequential tomotherapy IMRT technique (Peacock) and daily computer-assisted transabdominal ultrasonography (BAT) for target localization. Patients were instructed to maintain a full bladder and were placed in the supine position using triangulation tattoos and a leg immobilizer to minimize pelvic rotation. The BAT ultrasound system is docked to the treatment collimator and electronically imports the CT simulation target contours and isocenter. The system is able to use the machine isocenter as a reference point to overlay the corresponding CT contours onto the ultrasound images captured in the transverse and sagittal planes. A touch screen menu is used to maneuver the CT contours in three dimensions such that they match the ultrasound images. The system then displays the three-dimensional couch shifts required to produce field alignment. Data were prospectively collected to measure the frequency by which useful ultrasound images were obtained, the amount of time required for localization/setup, and the direction/magnitude of the positional adjustments. RESULTS: Of the 23 patients, the BAT ultrasound system produced images of sufficient quality to perform the overlay of the CT contours in 19 patients such that positional verification could be reliably performed. Poor image quality was associated with patient inability to maintain a full bladder, large body habitus, or other anatomic constraints. Of the 19 assessable patients, a total of 185 treatment alignments were performed (mean 8.8/patient). For all cases, the average time required for the daily ultrasound imaging and positional adjustments was 11.9 min. After the initial 5 cases, the user experience skills improved such that the time required for image verification/positional adjustments decreased to a mean of 5.6 min. The average right-left, AP, and cranial-caudal adjustment was 2.6 +/- 2.1 mm, 4.7 +/- 2.7 mm, and 4.2 +/- 2.8 mm, respectively. Positional adjustments >10 mm were infrequent and related primarily to misidentification of the target structures on the ultrasound image, patient movement, or improper registration of the triangulation tattoos. CONCLUSION: Daily computer-assisted BAT ultrasound positional verification of the prostate can be successfully performed through the acquisition of high-quality images in most patients with only a modest increase in treatment setup time. Positional data obtained with this system resulted in clinically meaningful adjustments in daily setup for sequential IMRT that would not be otherwise apparent from other verification modalities.

Algorithms↗
PubMed2002

Preliminary results of a phase I/II study of HDR brachytherapy alone for T1/T2 breast cancer.

PURPOSE: To investigate the feasibility, toxicity, cosmetic outcome, and local control of high-dose-rate (HDR) brachytherapy alone without whole breast external beam irradiation for early-stage breast carcinoma. METHODS AND MATERIALS: Between June 1997 and August 1999, 32 women diagnosed with a total of 33 AJCC Stage I/II breast carcinomas underwent surgical breast excision and postoperative irradiation using HDR brachytherapy interstitial implantation as part of a multi-institutional clinical Phase I/II protocol. Eligible patients included those with T1, T2, N0, N1 (< or =3 nodes positive), and M0 tumors of nonlobular histologic features with negative surgical margins, no extracapsular lymph node extension, and a negative postexcision mammogram. Brachytherapy catheters were placed at the initial excision, reexcision, or either sentinel or full-axillary sampling. Direct visualization, surgical clips, and ultrasound and/or CT scan assisted in the delineation of the target volume, defined as the excision cavity plus a 2-cm margin. High-activity 192Ir (3-10 Ci) was used to deliver 340 cGy/fraction, 2 fractions/d, for 5 consecutive days, to a total dose of 34 Gy to the target volume. Source position and dwell times were calculated using standard volume optimization techniques. RESULTS: The median follow-up of all patients was 33 months, and the mean patient age was 63 years. The mean tumor size was 1.3 cm, and 55% had an extensive intraductal component. Three patients had positive axillary nodes. Two patients experienced moderate perioperative pain that required narcotic analgesics. No peri- or postoperative infections occurred. No wound healing problems and no significant skin reactions related to the implant developed. The Radiation Therapy Oncology Group late radiation morbidity scoring scheme was applied to the entire 33-case cohort. In the assessment of the skin, 30 cases were Grade 0-1 and 3 cases were Grade 2. Subcutaneous toxicity was scored as 11 patients with Grade 0, 3 with Grade 1, 8 with Grade 2, 3 with Grade 3, and 8 with Grade 4. Clinically evident fat necrosis occurred in 8 patients at a median of 7.5 months after HDR brachytherapy completion. The only variables significantly associated with Grade 3-4 toxicity were the number of source dwell positions and the volume of tissue encompassed by the prescription isodose shell. The global cosmetic scores after a minimum of 18 months' follow-up were 0 cases with poor, 4 with fair, 5 with good, and 24 with excellent scores. One case of ipsilateral breast tumor recurrence was diagnosed 23 months after HDR brachytherapy, for a 4-year actuarial recurrence rate of 3%. This failure appeared to be a new primary tumor, because it was histologically distinct from the initial tumor and was located 9 cm from the initial tumor bed and 3 cm from the edge of the implant volume. CONCLUSION: Radiotherapy of the tumor bed alone with HDR interstitial brachytherapy is associated with a 33% incidence of Grade 3-4 s.c. toxicity, but with generally favorable overall cosmetic results. The risk of toxicity appears to be primarily related to the implant volume. With limited follow-up, the incidence of ipsilateral breast tumor recurrence was low.

Adult↗
PubMed2002

Human papillomavirus E6-induced degradation of E6TP1 is mediated by E6AP ubiquitin ligase.

High-risk human papilloma viruses are known to be associated with cervical cancers. We have reported previously that the high-risk human papillomavirus (HPV) E6 oncoprotein interacts with E6TP1, a novel Rap GTPase-activating protein (RapGAP). Similar to p53 tumor suppressor protein, the high-risk HPV E6 oncoproteins target E6TP1 for degradation. The HPV16 E6-induced degradation of E6TP1 strongly correlates with its ability to immortalize human mammary epithelial cells. In this study, we used treatment with a proteasome inhibitor MG132, analysis in CHO-ts20 cells with a thermolabile ubiquitin-activating enzyme, and direct detection of ubiquitin-modified E6TP1 to demonstrate that E6TP1 is targeted for degradation by the ubiquitin-proteasome pathway both in the presence and in the absence of E6. Using deletion mutants of E6TP1, we mapped the region required and sufficient for E6 binding to COOH-terminal 40 amino acid residues and showed this region to be necessary for E6-dependent degradation of E6TP1. Furthermore, the E6-binding region of E6TP1 complexes with E6AP via E6. Importantly, the purified E6AP enhanced the ubiquitination and degradation of E6TP1 in the presence of E6 in vitro. Additionally, the expression of a dominant-negative E6AP mutant (C833A) in cells inhibited the E6-induced degradation of E6TP1. These findings demonstrate that the E6-induced decrease in the levels of E6TP1 protein involves the E6AP-mediated ubiquitination followed by proteasome-dependent degradation.

Animals↗
PubMed2002

The value of breast lumpectomy margin assessment as a predictor of residual tumor burden in ductal carcinoma in situ of the breast.

BACKGROUND: Margin width is considered the most important risk factor for local recurrence in ductal carcinoma in situ (DCIS) of the breast. The purpose of this report is to assess the predictive utility of lumpectomy specimen margin assessment for the presence and extent of residual DCIS. METHODS: Specimens from 253 DCIS cases with lumpectomy and reexcision were studied to determine to the probability of residual DCIS on reexcision. The probability of residual tumor was evaluated with respect to tumor size, margin status, nuclear grade, presence of necrosis, patient age, and the extent of specimen processing (number of sections/volume tissue). Lesions were grouped by size: less than or equal to 2 mm, greater than 2-15 mm, greater than 15-40 mm, or greater than 40 mm. Margin width was recorded as the distance of DCIS to the closest specimen edge or, for positive margins, scored as: extensive (margin involvement in > or =8 sections or >4 low-power fields [LPFs]), moderate (5-7 sections or 2-4 LPFs), minimal (2-4 sections or 1 LPF), or focal (1 section, single focus). The amount of residual tumor was graded by maximum dimension on a semiquantitative basis. RESULTS: Initial excision margin significantly predicted for the presence of residual tumor on reexcision. Residual tumor was found on reexcision in 85% of extensively positive, 68% of moderately positive, 46% of minimally positive, 30% of focally positive, 41% of greater than 0-1 mm, 31% of greater than 1-2 mm, and 0% of greater than 2 mm margins (P < 0.0001). On univariate analysis, margin width and lesion size of initial excision specimens significantly predicted for the presence of residual DCIS on reexcision. Age, grade, necrosis, and extent of specimen processing were not significant prognostic factors. On multivariate analysis, both initial margin width (P < 0.0001) and lesion size (P = 0.02) significantly predicted for residual DCIS. As for amount of residual tumor, margin width and initial lesion dimension both significantly predicted for medium to large residuum, whereas age 45 years or younger was of borderline significance on univariate analysis. On multivariate analysis, margin width and lesion size on initial excision both remained significant predictors of larger volume residual tumor. CONCLUSIONS: The margin status of a DCIS lumpectomy specimen is the most important predictive factor for both the presence and amount of residual disease.

Adult↗
PubMed2002

Accelerated partial breast irradiation: an updated report from the American Brachytherapy Society.

Logistical barriers of time and travel created by the conventional six week course of radiotherapy prevent many women from pursuing breast conservation treatment. For the past 12 years, Accelerated Partial Breast Irradiation (APBI) has been investigated as a potential alternative treatment approach in women with early stage breast cancer. The ability to complete treatment in five days has the potential to provide additional women with the option of breast conservation. The validity of this APBI is supported in the study of in-breast recurrence patterns, pathologic data and the clinical treatment experience. The review of the recent data on contemporary APBI reveals that patient selection criteria and brachytherapy quality assurance are clearly critical components and necessary to assure a successful treatment outcome. This updated report from the American Brachytherapy Society on Accelerated Partial Breast Irradiation reviews the appropriate background data supporting this treatment approach with conclusions regarding patient selection criteria and treatment delivery.

Advisory Committees↗
PubMed2002

Molecular biology and genetics of breast cancer development: a clinical perspective.

Understanding the molecular and genetic events affecting breast cancer development not only helps oncologists address important questions commonly asked by their patients but also helps clinicians gain insights into the biology of the disease. Although the molecular and genetic determinants of most sporadic breast cancer remain unknown, significant advances in the understanding of events that contribute to breast cancer formation have been made. It is now recognized that mutations in some tumor suppressor genes, such as p53, BRCA1, BRCA2, PTEN, or ATM, or epigenetic functional inactivation of other tumor suppressor genes, such as SYK and NES1, appear to play important early roles in the formation of some breast cancers. In addition, alterations in proto-oncogenes, such as HER2/neu, may contribute to the development of some breast cancer. The goal of this article is to further introduce clinicians to molecular and genetic pathways that contribute to breast cancer formation. By participating in the study of breast cancer development at the molecular as well as the histopathological level, oncologists can help develop novel prevention, diagnostic, and therapeutic approaches for the future.

Breast Neoplasms↗
PubMed2002

Human papillomavirus oncoprotein E6 inactivates the transcriptional coactivator human ADA3.

High-risk human papillomaviruses (HPVs) are associated with carcinomas of the cervix and other genital tumors. The HPV oncoprotein E6 is essential for oncogenic transformation. We identify here hADA3, human homologue of the yeast transcriptional coactivator yADA3, as a novel E6-interacting protein and a target of E6-induced degradation. hADA3 binds selectively to the high-risk HPV E6 proteins and only to immortalization-competent E6 mutants. hADA3 functions as a coactivator for p53-mediated transactivation by stabilizing p53 protein. Notably, three immortalizing E6 mutants that do not induce direct p53 degradation but do interact with hADA3 induced the abrogation of p53-mediated transactivation and G(1) cell cycle arrest after DNA damage, comparable to wild-type E6. These findings reveal a novel strategy of HPV E6-induced loss of p53 function that is independent of direct p53 degradation. Given the likely role of the evolutionarily conserved hADA3 in multiple coactivator complexes, inactivation of its function may allow E6 to perturb numerous cellular pathways during HPV oncogenesis.

Antineoplastic Agents↗