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Biomedical subjects

R C Bast

Publications and source records attributed to R C Bast.

At least 19 recordsLinked to original sources
PubMed2006

HER2 signaling modulates the equilibrium between pro- and antiangiogenic factors via distinct pathways: implications for HER2-targeted antibody therapy.

We determined the impact of HER2 signaling on two proangiogenic factors, vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8), and on an antiangiogenic factor, thrombospondin-1 (TSP-1). Re-expression of HER2 in MCF-7 and T-47D breast cancer cells that endogenously express low levels of HER2 resulted in elevated expression of VEGF and IL-8 and decreased expression of TSP-1. Inhibition of HER2 with a humanized anti-HER2 antibody (trastuzumab, or Herceptin) or a retrovirus-mediated small interfering RNA against HER2 (siHER2) decreased VEGF and IL-8 expression, but increased TSP-1 expression in BT474 breast cancer cells that express high levels of HER2. These in vitro results were further evaluated by treatment of BT474 xenografts in immunosuppressed mice with trastuzumab. Trastuzumab inhibited growth of BT474 xenografts and decreased microvascular density associated with downregulation of VEGF and IL-8 and with upregulation of TSP-1 expression. Inhibiting the PI3K-AKT pathway decreased VEGF and IL-8 expression. AKT1 overexpession increased VEGF and IL-8 expression, but did not increase TSP-1 expression. A p38 kinase inhibitor, SB203580, instead blocked TSP-1 expression and a p38 activator, MKK6, increased TSP-1 expression. Trastuzumab stimulated sustained p38 activation and SB203580 attenuated the TSP-1 upregulation induced by trastuzumab. HER2 signaling therefore influences the equilibrium between pro- and antiangiogenic factors via distinct signaling pathways. Trastuzumab inhibits angiogenesis and tumor growth, at least in part, through activation of the HER2-p38-TSP-1 pathway and inhibition of the HER2-PI3K-AKT-VEGF/IL-8 pathway.

Animals↗
PubMed2004

Analysis of 96 patients with advanced ovarian carcinoma treated with high-dose chemotherapy and autologous stem cell transplantation.

The purpose of this study was to identify characteristics significant to survival and progression-free survival in patients with advanced ovarian cancer receiving high-dose chemotherapy. In all, 96 patients received autologous stem cell transplantation. Regimens included paclitaxel with carboplatin (PC), topotecan, melphalan, cyclophosphamide (TMC) and cyclophosphamide, BCNU, thiotepa (CBT). At the time of transplantation, 43% of patients were in clinical CR, 34% were in clinical PR, 18% had progressive disease and 5% had stable disease. There were no treatment-related deaths. The 6-year survival by Kaplan-Meier was 38%. For patients who received transplantation for remission consolidation, the 6-year survival was 53% with a PFS of 29%. On univariate analysis, the CBT regimen, clear cell histology and disease status other than CR prior to treatment were statistically significant adverse prognostic factors. This analysis has demonstrated that patients in clinical remission are most likely to benefit from autologous transplantation, with the exception of patients with clear cell histology. The TMC combination appeared to be superior to the PC and CBT combinations. Comparative studies of different consolidation approaches will be necessary to determine if autologous transplantation is the preferred treatment for this patient population.

Adult↗
PubMed2003

Current research and treatment for epithelial ovarian cancer. A Position Paper from the Helene Harris Memorial Trust.

In March 2003, an international mulltidisciplinary group of scientists and clinicians with a specific interest in ovarian cancer met for 4 days to discuss research into and treatment of this challenging disease. Under the headings of molecular genetics, molecular biology, the biology of ovarian cancer, old therapies, new targets and the early detection of the disease, this Position Paper summarises the presentations and discussion from the 9th Biennial Helene Harris Memorial Trust Forum on Ovarian Cancer. In particular, we highlight the potential of international collaborations in translating laboratory science into useful clinical interventions.

Antineoplastic Agents↗
PubMed2002

Heregulin-induced apoptosis.

Heregulins (HRGs) are a group of polypeptide factors that are encoded by four different HRG genes that can express multiple isoforms through alternate RNA splicing. A number of HRG isoforms possess both growth stimulatory and growth inhibitory functions that are necessary for their important role in the development and maintenance of the heart, nervous system and epithelial cells in multiple organs including the breast. Growth inhibition by HRG relates to its ability to induce apoptosis, differentiation, and cell cycle G(2) arrest. Current studies suggest that HRGs can induce a unique form of apoptosis. In this article, we review recent progress in characterizing and understanding HRG-induced apoptosis. Particular attention has been given to: (1). the activation of caspases-7 and -9; (2). the role of the anti-apoptotic Bcl-2 protein; and (3). the signaling molecules and pathways that regulate HRG-induced apoptosis, including the p38, JNK, mTOR kinase, and PKC alpha kinase.

Alternative Splicing↗
PubMed2001

Heregulin-induced apoptosis is mediated by down-regulation of Bcl-2 and activation of caspase-7 and is potentiated by impairment of protein kinase C alpha activity.

Heregulins are a group of growth factors that play diverse and critical roles in the signaling network of the human epidermal growth factor receptor (HER or EGFR) superfamily. Our earlier studies have shown that recombinant heregulinbeta1 (HRG) induces apoptosis in SKBr3 breast cancer cells that overexpress HER2. Here we report molecular mechanisms of HRG-induced apoptosis. HRG treatment of SKBr3 cells for 72 h decreased the level of Bcl-2 protein. HRG treatment led to degradation of poly (ADP-ribose) polymerase (PARP) and activated both caspase-9 and caspase-7. No significant activation of caspase-3, -6, or -8 was detected. Expression of exogenous caspase-7 by adenovirus-caspase-7 (Ad-casp-7) in SKBr3 cells resulted in apoptosis, which mimicked the effect of HRG treatment. Expression of exogenous caspase-7 had no impact on Bcl-2 expression, but promoted PARP degradation. Two highly selective inhibitors of protein kinase C (PKC), GF109203X (GF) and Ro318425 (Ro), significantly enhanced HRG-induced apoptosis as determined by flow cytometric analysis and DNA fragmentation assay. Accordingly, the PKC inhibitor GF further decreased the level of Bcl-2 protein and further degraded PARP in HRG-treated cells. Assay of PKC activity indicated that HRG activated PKC in SKBr3 cells, predominantly affecting the PKCalpha isoform. To confirm which PKC isoform(s) mediated potentiation of HRG-induced apoptosis, the profile of PKC isoforms was measured in SKBr3 cells. Five PKC isoforms, PKCalpha, PKCiota, PKCzeta, PKClambda, and PKCdelta as well as their receptors (RACK1) were expressed in this cell line. Treatment with PKC inhibitors GF and Ro decreased protein levels of both PKCalpha and PKCdelta at 24 h. PKCalpha levels were still depressed at 72 h. GF and Ro had little effect on the expression of other PKC isoforms. An inhibitor of classical PKC isoforms (Go6976) enhanced HRG-induced apoptosis, whereas the PKCdelta selective inhibitor rottlerin did not. As PKCalpha was the only classical isoform expressed in SKBr3 cells, the effect of Go6976 on HRG-induced apoptosis largely related to inhibition of PKCalpha. Constitutive expression of wild-type PKCalpha attenuated the apoptosis produced by HRG and GF. Consequently, HRG-induced apoptosis in SKBr3 cells appeared to involve down-regulation of Bcl-2 protein, activation of caspase-9 and caspase-7, and degradation of PARP. Inhibition of PKC function enhanced HRG-induced apoptosis, leading to synergistic down-regulation of Bcl-2 expression. Impairment of the PKCalpha isoform alone was sufficient to potentiate HRG-induced apoptosis.

Apoptosis↗
PubMed2001

OVX1, macrophage-colony stimulating factor, and CA-125-II as tumor markers for epithelial ovarian carcinoma: a critical appraisal.

BACKGROUND: Ovarian carcinoma remains the leading cause of death from gynecologic malignancy in Australia, the Netherlands, and the United States. CA-125-II, the most widely used serum marker, has limited sensitivity and specificity for detecting small-volume, early-stage disease. Therefore, a panel of three serum tumor markers-OVX1, CA-125-II, and macrophage-colony stimulating factor (M-CSF)-has been used to evaluate the sensitivity and specificity of multiple markers for the detection of early-stage ovarian carcinoma. METHODS: Preoperative serum levels of OVX1, CA-125-II, and M-CSF were measured in 281 patients with primary ovarian epithelial tumors of different histotypes. Among these tumors, 175 were malignant, 29 were of borderline malignancy, and 77 were benign. The three markers also were measured in sera from 117 apparently healthy women. Marker levels were considered abnormal at CA-125-II > 35 U/mL, OVX1 > 7.2 U/mL, and M-CSF > 3.5 ng/mL. RESULTS: Among 175 women with malignant ovarian tumors, at least one of the three serum markers was elevated in 85%, whereas CA-125-II was elevated in 80% (P = 0.008). In 58 patients with Stage I ovarian carcinoma, at least one of the three serum markers was elevated in 76%, whereas CA-125 levels were elevated in 66% (P = 0.04). For patients with borderline and benign tumors, a combination of the three antigens had slightly higher sensitivity compared with CA-125-II, but the differences were not statistically significant. Among 117 apparently healthy women, CA-125-II was elevated in 4%, and one of the three markers was positive in 17%. CONCLUSIONS: The sensitivity of a combination of three serum markers was significantly greater than the sensitivity of the CA-125-II assay alone in patients with primary ovarian epithelial tumors of different histotypes. This was true for all stages, including early-stage, potentially curable disease. When used as single markers, however, only the CA-125-II assay could distinguish invasive Stage I tumors from apparently healthy women.

Antigens, Tumor-Associated, Carbohydrate↗
PubMed2001

Genetic analysis of early- versus late-stage ovarian tumors.

In the United States, ovarian cancer is the fourth most common cause of cancer-related deaths among women. The most important prognostic factor for this cancer is tumor stage, or extent of disease at diagnosis. Although women with low-stage tumors have a relatively good prognosis, most women diagnosed with late-stage disease eventually succumb to their cancer. In an attempt to understand early events in ovarian carcinogenesis, and to explore steps in its progression, we have applied multiple molecular genetic techniques to the analysis of 21 early-stage (stage I/II) and 17 advanced-stage (stage III/IV) ovarian tumors. These techniques included expression profiling with cDNA microarrays containing approximately 18,000 expressed sequences, and comparative genomic hybridization to address the chromosomal locations of copy number gains as well as losses. Results from the analysis indicate that early-stage ovarian cancers exhibit profound alterations in gene expression, many of which are similar to those identified in late-stage tumors. However, differences observed at the genomic level suggest differences between the early- and late-stage tumors and provide support for a progression model for ovarian cancer development.

Disease Progression↗
PubMed2001

Genomic structure and promoter characterization of an imprinted tumor suppressor gene ARHI.

We have recently identified a maternally imprinted tumor suppressor gene, ARHI (aplysia ras homolog I), the expression of which is lost in ovarian and breast cancers. We have now characterized the genomic structure of the gene including its promoter and the methylation status of its upstream CpG islands. The ARHI gene spans approximately 8 kb containing two exons and one intron. Exon 1 contains 81 non-translated nucleotides, connected to exon 2 with a 3.2-kb intron. The entire protein-coding region is located within exon 2 and encodes a 229-residue small GTP-binding protein belonging to the Ras superfamily. Genomic structure analysis has identified three potential CpG islands. Two of them (CpG island I and II) are located within the promoter and adjacent exon 1 of the ARHI gene. Aberrant methylation of these CpG islands has been detected in breast cancer cells but not in normal epithelial cells, supporting the possibility that appropriate methylation status of the CpG islands in the promoter region may play a role in the downregulation of ARHI gene expression. A TATA box is found 27 bp upstream of the transcription start site associated with several putative transcription factor binding sites. Transient transfection with nested deletion constructs of the 2-kb ARHI promoter regions fused to a luciferase reporter indicated a 121-bp sequence upstream of the transcription initiation site is required for basal promoter activity. Interestingly, this is the region where lower promoter activity has been observed in cancer cells than in normal cells.

Amino Acid Sequence↗
PubMed2001

Phase I study of stealth liposomal doxorubicin in combination with gemcitabine in the treatment of patients with metastatic breast cancer.

PURPOSE: We conducted a single-institution phase I clinical trial to determine the maximum-tolerated dose (MTD) and define the toxic effects of stealth liposomal doxorubicin in combination with gemcitabine in patients with metastatic breast cancer. PATIENTS AND METHODS: Patients were eligible if they had disease progression with no limit on prior number of chemotherapy regimens. Prior treatment with liposomal doxorubicin and/or gemcitabine was not allowed. The starting dose of liposomal doxorubicin was 20 mg/m(2) on day 1 only with a 20% dose escalation of the previous mg/m(2) dose until MTD was reached. Gemcitabine was given as a fixed dose of 800 mg/m(2) on days 1 and 8 every 3 weeks. RESULTS: We treated 27 patients of whom six had never received chemotherapy for their disease. Most had had visceral involvement as their dominant site of disease. The dose-limiting toxicity was myelosuppression, which included neutropenia and thrombocytopenia. However, neither neutropenic fever nor episodes of bleeding were major occurrences. Significant antitumor activity was also observed with a total of two complete and seven partial responses. The recommended phase II dose is liposomal doxorubicin 24 mg/m(2) on day 1 and gemcitabine 800 mg/m(2) on days 1 and 8 every 21 days. CONCLUSION: The combination of liposomal doxorubicin and gemcitabine is an active and well tolerated regimen when administered on a 21-day schedule. Myelosuppression limited further dose escalation, however, it did not increase the incidence of neutropenic fever. Significant antitumor activity seen in heavily and minimally pretreated patients warrants further evaluation of this combination.

Adult↗
PubMed2001

2000 update of recommendations for the use of tumor markers in breast and colorectal cancer: clinical practice guidelines of the American Society of Clinical Oncology.

OBJECTIVE: To update the 1997 clinical practice guidelines for the use of tumor marker tests in the prevention, screening, treatment, and surveillance of breast and colorectal cancers. These guidelines are intended for use in the care of patients outside of clinical trials. OPTIONS: Six tumor markers for colorectal cancer and eight for breast cancer were considered. They could be recommended or not for routine use or for special circumstances. In addition to carcinoembryonic antigen (CEA) and CA 15-3, CA 27.29 was also considered among the serum tumor markers for breast cancer. OUTCOMES: In general, the significant health outcomes identified for use in making clinical practice guidelines (overall survival, disease-free survival, quality of life, lesser toxicity, and cost-effectiveness) were used. EVIDENCE: A computerized literature search from 1994 to March 1999 was performed. VALUES: The same values for use, utility, and levels of evidence were used by the committee. BENEFITS, HARMS, AND COSTS: The same benefit, harms, and costs were used. RECOMMENDATION: Changes were recommended (see Appendix). VALIDATION: The updated recommendations were validated by external review by the American Society of Clinical Oncology's (ASCO's) Health Services Research Committee and by ASCO's Board of Directors. SPONSOR: American Society of Clinical Oncology.

Adult↗
PubMed2001

Fluorescence spectroscopy for in vivo characterization of ovarian tissue.

BACKGROUND AND OBJECTIVE: The objective of this study was to explore whether fluorescence spectroscopy signatures differed between normal variations within the ovary, benign neoplasms, and ovarian cancer. STUDY DESIGN/MATERIALS AND METHODS: Ovarian tissue fluorescence emission spectra were collected sequentially at 18 excitation wavelengths ranging from 330 to 500 nm from 11 patients undergoing oophorectomy and assembled into fluorescence excitation emission matrices (EEMs); biopsies corresponded to the area interrogated. Spectral areas that could differentiate normal ovary, benign neoplasms, and cancers were evaluated, using histopathology as the reference standard. RESULTS: The most promising measurements are (1) the integrated fluorescence intensity from 400 to 430 nm excitation at 460 nm emission, and (2) the ratios of fluorescence intensities at 330 nm excitation, 385 and 500 nm emission, and at 375 and 415 nm excitation, 460 nm emission. Simple systems to visualize these optical signatures at laparoscopy could be designed. CONCLUSION: Fluorescence spectroscopy may have the ability to distinguish ovarian cancers from normal ovarian structures and benign neoplasms, as well as differentiate between normal variations and metaplastic structures and should be further explored as a device for the early detection of ovarian cancers.

Female↗
PubMed2001

Synergistic interaction between an anti-p185HER-2 pseudomonas exotoxin fusion protein [scFv(FRP5)-ETA] and ionizing radiation for inhibiting growth of ovarian cancer cells that overexpress HER-2.

OBJECTIVES: The HER-2 proto-oncogene is overexpressed in 15-30% of ovarian cancers, providing a target for therapy in a fraction of patients. We previously described the ability of a recombinant single-chain anti-p185HER-2-Pseudomonas exotoxin A fusion protein, scFv(FRP5)-ETA, to inhibit growth of cancer cells in culture and tumor xenografts in vivo. We have also described synergistic interaction between an anti-p185HER-2-ricin A chain immunotoxin and ionizing radiation for inhibiting growth of ovarian and breast cancer cells that overexpress HER-2. Our objective in this report was to evaluate the in vitro and in vivo effects of scFv(FRP5)-ETA against SKOv3 ovarian cancer cells that have been transfected to express >10(6) p185HER-2 receptors per cell (clone-9002-18). METHODS: Inhibition of clonogenic growth was measured in vitro by limiting dilution analysis. Inhibition of tumor growth was measured in vivo using heterografts established with the same ovarian cancer cell lines. RESULTS: Clone-9002-18 cells were substantially more sensitive than parental SKOv3 cells to the cytotoxic effects of scFv(FRP5)-ETA. Exotoxin fusion protein induced apoptosis in clone-9002-18 cells, but did not affect parental SKOv3 cells. Treatment of clone-9002-18 cells with 200- to 2000-cGy external beam irradiation in combination with scFv(FRP5)-ETA produced synergistic elimination of clonogenic tumor cells in culture. In vivo, subcutaneous or intraperitoneal growth of tumor xenografts in nu/nu mice was significantly inhibited (P = 0.004) by treatment for 10 days with scFv(FRP5)-ETA or with 131I-labeled-520C9 anti-p185HER-2 radionuclide conjugate, but additive effects were not observed with combined treatment. CONCLUSION: ScFv(FRP5)-ETA deserves further evaluation for intraperitoneal therapy of ovarian cancers that overexpress p185HER-2.

ADP Ribose Transferases↗
PubMed2001

Regulation of invasion of epithelial ovarian cancer by transforming growth factor-beta.

OBJECTIVE: The metastatic process in epithelial ovarian cancer is thought to involve surface shedding and subsequent dissemination of ovarian cancer cells, facilitated by localized proteolysis at the interface between ovarian cancer cells and peritoneal surfaces. The factors regulating the metastatic process, however, are not well understood. Transforming growth factor-beta (TGF-beta) is a multifunctional peptide that elicits numerous cellular effects pertinent to the metastatic process. The purpose of this study was to evaluate the regulatory role of TGF-beta on metastasis in ovarian cancer. METHOD: We evaluated the effect of TGF-beta on the metastatic characteristics (adhesion, invasion, motility, proteolysis) of five ovarian cancer cell lines (DOV-13 and OVCA 420, 429, 432, and 433), two short-term primary ovarian cancer cell cultures (OVCA 10 and OVCA 208), and five normal ovarian surface epithelial (NOSE) cell cultures (OSE 133, 185, 186, 188, and 189). The effect of TGF-beta on invasion and proteolysis was quantified using a modified Boyden chamber invasion assay, zymography, a coupled colorimetric activity assay, and an HPLC-based quantitation of synthetic substrate cleavage. RESULTS: TGF-beta significantly increased invasion in five of seven ovarian cancer cell lines in amounts ranging from 2- to 20-fold. In contrast, TGF-beta significantly decreased invasion in two of five NOSE isolates by 50 to 80% and had no significant effect on invasion in three. TGF-beta treatment increased matrix metalloproteinase (MMP) expression in OVCA 420 and 433 and DOV-13, resulting in MMP-dependent collagen cleavage and invasive activity. Addition of the MMP inhibitor GI12947 neutralized the enhancing effect of TGF-beta on invasion. TGF-beta had no effect on ovarian cancer cell motility and only increased adhesion in DOV-13. CONCLUSIONS: These data suggest that TGF-beta may enhance the invasiveness of ovarian cancers through induction of MMP activity.

Basement Membrane↗
PubMed2001

High-dose topotecan, melphalan, and cyclophosphamide (TMC) with stem cell support: a new regimen for the treatment of advanced ovarian cancer.

OBJECTIVE: The goal of this study was to determine the optimal dose of topotecan when used in combination with high-dose melphalan and cyclophosphamide (TMC), and to assess the toxicity and efficacy of the regimen in patients with advanced ovarian cancer. METHODS: Fifty-three patients with persistent or recurrent ovarian cancer were treated. Disease status at study entry included: platinum-sensitive recurrent disease (15 patients), platinum-resistant or refractory recurrent disease (15 patients), positive second-look surgery (16 patients), failure to achieve a primary clinical complete response (CR) (7 patients). Following stem cell mobilization and collection, patients were given cyclophosphamide 1 g/m(2)/day on Days -6, -5, -4; melphalan 70 mg/m(2)/day on Days -3, -2; and topotecan at escalating doses from 1.25 to 4.0 mg/m(2)/day on Days -6 to -2. Peripheral blood stem cells were infused on Day 0. RESULTS: The optimal topotecan dose selected for future trials was 4.0 mg/m(2)/day x 5 days. The regimen had acceptable toxicity with no regimen-related death. Toxicity (Bearman toxicity criteria) was limited mostly to grade 1-2 mucositis and diarrhea. The overall response rate of patients with measurable or evaluable disease was 93%. Median survival has not yet been reached, but with a median follow up of 18 months (range: 11-37) 77% of patients are alive. CONCLUSION: With a topotecan dose of 4.0 mg/m(2)/day x 5 days, the TMC regimen has acceptable toxicity and produces high response rates. In the setting of ovarian cancer, high-dose chemotherapy should be administered only as part of well-designed clinical trials. TMC should be considered a potential regimen for future randomized trials in patients with advanced ovarian cancer.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2000

Functional evidence for an ovarian cancer tumor suppressor gene on chromosome 22 by microcell-mediated chromosome transfer.

The identity of many tumor suppressor genes important in epithelial ovarian cancer tumorigenesis remains unknown. In an effort to localize a novel tumor suppressor on chromosome 22, a psv2neo tagged human chromosome 22 was transferred into the malignant epithelial ovarian cancer cell line, SKOv-3, by microcell-mediated chromosome transfer. Complete suppression of the transformed phenotype was observed in 16 of 18 individual microcell hybrid clones as evidenced by the complete abrogation of cell growth under anchorage-independent conditions. In vitro doubling times were also dramatically reduced, as was the ability to form subcutaneous tumors in CD1 nu/nu mice. Only one polymorphic marker, D22S429, segregated with decreased transformation and tumorigenic potential, suggesting that an unrecognized tumor suppressor may localize to chromosome 22q11-q12. These data provide functional support for the presence of a novel tumor suppressor locus (or loci) on chromosome 22 that is important in ovarian cancer tumorigenesis.

Animals↗
PubMed2000

Inhibition of growth-factor-induced phosphorylation and activation of protein kinase B/Akt by atypical protein kinase C in breast cancer cells.

The protein kinase B/Akt serine/threonine kinase, located downstream of phosphoinositide 3-kinase (PI-3K), is a major regulator of cellular survival and proliferation. Atypical protein kinase C (aPKC) family members are activated by PI-3K and also contribute to cell proliferation, suggesting that Akt and aPKC might interact to activate signalling through the PI-3K cascade. Here we demonstrate that blocking PKC activity in MDA-MB-468 breast cancer cells increased the phosphorylation and activity of Akt. Functional PI-3K was required for the PKC inhibitors to increase Akt phosphorylation and activation, potentially owing to the activation of specific PKC isoforms by PI-3K. The concentration dependence of the action of the PKC inhibitors implicates aPKC in the inhibition of Akt phosphorylation and activity. In support of a role for aPKC in the regulation of Akt, Akt and PKCzeta or PKClambda/iota were readily co-precipitated from the BT-549 breast cancer cell line. Furthermore, the overexpression of PKCzeta inhibited growth-factor-induced increases in Akt phosphorylation and activity. Thus PKCzeta associates physically with Akt and decreases Akt phosphorylation and enzyme activity. The effects of PKC on Akt were transmitted through the PI-3K cascade as indicated by changes in p70 s6 kinase (p70(s6k)) phosphorylation. Thus PKCzeta, and potentially other PKC isoenzymes, regulate growth-factor-mediated Akt phosphorylation and activation, which is consistent with a generalized role for PKCzeta in limiting growth factor signalling through the PI-3K/Akt pathway.

Breast Neoplasms↗