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Biomedical subjects

M E Lippman

Publications and source records attributed to M E Lippman.

At least 199 records · Page 11Linked to original sources
PubMed1986

Estrogen-induced factors of breast cancer cells partially replace estrogen to promote tumor growth.

The hormone 17 beta-estradiol acts through its receptor system to induce MCF-7 human breast cancer cells to form tumors in athymic mice. In vitro studies have identified the production of estrogen-induced growth factors from MCF-7 cells that may have a role in growth control. These induced growth factors were sufficient to stimulate MCF-7 tumor growth in ovariectomized athymic mice, thus partially replacing estradiol. Growth factors may act as estrogen-induced "second messengers" in estrogen-responsive growth of human breast cancer.

Animals↗
PubMed1986

Transcriptional control of thymidine kinase gene expression by estrogen and antiestrogens in MCF-7 human breast cancer cells.

The mechanism by which estrogen and antiestrogens modulate cytoplasmic thymidine kinase (TK) activity has been studied in MCF-7 cells. Using a cloned cDNA probe for human TK, we have identified a single 1500-nucleotide transcript as the cytoplasmic TK-mRNA in MCF-7 cells. In normally cycling or synchronously growing cells, the level of this mRNA maximally increased 2-3-fold after 24 h of estradiol-17 beta (E2) stimulation and decreased below control level in the presence of antiestrogens. Neither E2 nor antiestrogens altered the size of TK-mRNA. Hormonal regulation of TK-mRNA paralleled changes in TK enzyme activity and [3H]thymidine incorporation. Using endogenous nuclear run-off transcription to investigate the expression of the human TK gene, we demonstrate that TK-mRNA levels were regulated by transcriptional control. Modulation of TK gene activity during the process of estrogen stimulation or antiestrogen inhibition was not accompanied by changes in the methylation pattern at internal sites of the TK gene. These results suggest a transcriptional control of human TK gene by E2 and antiestrogens in MCF-7 cells.

Amanitins↗
PubMed1986

8th San Antonio Breast Cancer Symposium--Plenary lecture. Autocrine and paracrine growth regulation of human breast cancer.

We consider the hypothesis that estrogen control of hormone dependent breast cancer is mediated by autocrine and paracrine growth factors secreted by the breast cancer cells themselves. Though we show direct, unmediated effects of estrogen on specific cell functions, we also provide evidence that human breast cancer cells secrete a collection of growth factors (IGF-I, TGF alpha, TGF beta, a PDGF-like competency factor, and at least one new epithelial colony stimulating factor). Some of these are estrogen-regulated in hormone dependent cells, and are constitutively increased in cells which acquire independence either spontaneously or by ras transfection. Collectively, the secreted growth factors are capable of promoting tumor formation by MCF-7 cells in nude mice, though not to the same extent as estrogens. There would seem to be potential for clinical intervention in the autocrine and paracrine control of breast cancer cells, including some cells which are no longer dependent on estrogens.

Breast Neoplasms↗
PubMed1986

Autocrine and paracrine growth regulation of human breast cancer.

Previous work from our laboratory has demonstrated that human breast cancer (BC) cells in culture can be stimulated by physiologic concentrations of estrogen. In an effort to further understand this process, we have examined the biochemical and biological properties of proteins secreted by human BC cells in vitro. We have developed a defined medium system which simultaneously allows the collection of factors secreted by the BC cells, facilitates their purification and allows for an unequivocal assay of their effect on other BC cells. By both biochemical and radioimmunoassay procedures, MCF-7 cells secrete large quantities of IGF-I-like activity. The cells contain receptors for IGF-I and are stimulated by physiologic concentrations of IGF-I. Multiple additional peaks of growth stimulatory activity can be obtained by partial purification of conditioned media from human BC cells by sequential dialysis, acid extraction and Biogel P60 chromatography. These peaks are induced up to 200-fold by physiologic concentrations of estrogen. Several of these peaks cross-react in a radioreceptor assay with EGF and are thus candidates for transforming growth factors. Monoclonal antibodies (MCA) have been prepared which react with secreted proteins from the MCF-7 cells. One of these MCAs binds to material from MCF-7 and ZR-75-1 hormone-dependent BC cells only when these two lines are treated with estrogen but reacts with conditioned medium from several other hormone-independent cell lines in the absence of estrogen stimulation. This MCA is currently undergoing further characterization and evaluation of its biological potency. We conclude that with estrogen stimulation, hormone-dependent human BC cells secrete peptides which when partially purified can replace estrogen as a mitogen. Their role as autocrine or paracrine growth factors and their effects on surrounding nonneoplastic stroma may suggest a means of interfering with tumor proliferation.

Animals↗
PubMed1986

17 beta-estradiol regulates and v-Ha-ras transfection constitutively enhances MCF7 breast cancer cell interactions with basement membrane.

The interaction of a line of human breast carcinoma cells (MCF7) with basement membrane components, particularly laminin, was altered by exposure of the cells to estrogen as well as by transfection of the cells with the v-Ha-ras oncogene. In both cases, the cells show a greater ability to attach to a laminin substrate, to migrate to laminin, to grow in the presence of a basement membrane matrix, and to cross barriers of reconstituted basement membrane. These responses were associated with an increase in the expression of laminin receptors. It is postulated that the increase in the invasive behavior of the cells treated with estrogen or transfected with v-Ha-ras is related to the increased number of laminin receptors and their interaction with laminin. Estrogen had no discernible effect on the v-Ha-ras transfected cells. It appears that in the MCF7 cells, the malignant phenotype is under hormonal control and that this control is bypassed after v-Ha-ras transfection.

Basement Membrane↗
PubMed1986

Complete axillary lymph node dissection for stage I-II carcinoma of the breast.

We reviewed the complete axillary dissection specimens of 136 patients with stage I-II breast cancer to clarify the distribution of axillary lymph node metastases in this disease. Our series included 71 patients undergoing axillary dissection as part of a modified radical mastectomy (MRM) and 65 patients undergoing axillary dissection in conjunction with conservative surgery of the breast and definitive postoperative breast radiotherapy (CAD). These two groups of patients were comparable according to age, menopausal status, tumor size, and clinical stage. In all patients the pectoralis minor muscle was excised and all axillary tissue removed. Each specimen contained a median of 23 lymph nodes. The axillary levels (I, II, III) were determined according to the relationship of axillary tissue to the pectoralis minor muscle (lateral, inferior, medial). Thirty-nine percent of the lymph nodes were contained in level I, 41% in level II, and 20% in level III. There were no significant differences noted in the number of lymph nodes or in the distribution of lymph nodes according to axillary level between dissections performed as part of the MRM or those done as a single procedure (CAD). Sixty-five patients (47.8%) had one or more positive lymph nodes in their axillary specimen. The clinical and pathologic stage was determined and compared for all patients. Among patients judged to have a clinically negative axilla, 37.6% had histologically positive lymph nodes (clinical false-negative rate). For patients with a clinically positive axilla, 11.1% had, histologically, no evidence of metastatic disease (clinical false-positive rate). When the distribution of lymph node metastases according to axillary level was studied, it was found that 29.2% of lymph node-positive patients (or 14.0% of all patients) had metastases only to level II and/or III of the axilla, with level I being negative (skip metastases). This incidence of skip metastases was greater among clinically node-negative than among clinically node-positive patients, but was not related to the size or location of the primary tumor in the breast. In addition, it was found that 20.0% of lymph node-positive patients (or 9.6% of all patients) were converted from three or fewer to four or more positive nodes by analysis of lymph nodes contained in levels II and III. This conversion from three or fewer to four or more positive nodes was due primarily to information contained in level II, with level III contributing to a smaller degree.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1986

Induction of epidermal growth factor-related polypeptides by 17 beta-estradiol in MCF-7 human breast cancer cells.

MCF-7 human breast cancer cells release polypeptides related to insulin-like growth factor-I (IGF-I) and epidermal growth factor (EGF) into serum-free culture medium (CM). Treatment of MCF-7 cells with 17 beta-estradiol, which is required in vivo for MCF-7 tumor growth in the nude mouse and stimulates the MCF-7 growth rate in vitro, resulted in selectively enhanced growth factor activities in CM. Autostimulatory growth-promoting activity was elevated at least 2-fold, and EGF-like polypeptides were elevated 5-fold but IGF-I immunoreactivity was not elevated. Several species of estrogen-induced receptor-reactive EGF-like polypeptides, suggestive of high molecular weight transforming growth factor alpha, were detected after gel exclusion chromatography of CM extracted with 1 M acetic acid. A 30,000 mol wt peak of EGF receptor competing activity comigrated with a peak of autostimulatory and fibroblast-transforming activity. It is possible that estradiol stimulation of MCF-7 growth and/or tumor formation may depend on induction of EGF-related polypeptide growth factors. EGF-I- and EGF-related polypeptides may act together as autocrine or paracrine growth factors in breast cancer.

Breast Neoplasms↗
PubMed1986

Characterization of estrogen responsive transforming activity in human breast cancer cell lines.

We have characterized the production of transforming growth factor (TGF) activities by five human breast cancer cell lines in culture. The presence of TGF-alpha and -beta activity in medium conditioned by these cells was detected by induction of anchorage-independent colony formation of normal rat kidney cells in soft agar and by epidermal growth factor and TGF-beta receptor competition studies. In MCF-7, an estrogen-receptor positive cell line which requires estrogen for tumorigenesis in vivo, 17 beta-estradiol induced a 2-5-fold increase in a TGF-alpha-like activity (apparent molecular weight, 68,000 and 30,000 by column chromatography). An estrogen induction of lower magnitude (1.5-2.5-fold) was also seen in two other estrogen responsive cell lines, ZR-75-B and T47D. TGF-beta was not induced by 17 beta-estradiol in any of the three cell lines and was decreased by up to 50% of control in the MCF-7 and T47D cell lines. TGF-beta was not detectable by radioreceptor assay in the ZR-75-B cell line. Two hormone-independent and highly tumorigenic cell lines were studied. The MDA-MB-231 cell line produced large amounts of both TGF-alpha-like (Mr 30,000) and TGF-beta activities. In the HS578T cell line, little TGF-alpha was detectable, while large amounts of TGF-beta were produced. No simple correlations between the tumorigenicity of the cell lines in nude mice and production of either TGF activity could be demonstrated.

Animals↗
PubMed1986

Treatment of locally advanced breast cancer using primary induction chemotherapy with hormonal synchronization followed by radiation therapy with or without debulking surgery.

Fifty-one patients with stage IIIA or IIIB locally advanced breast cancer received primary induction chemotherapy (hormonal synchronization, 46 patients) to a maximum objective clinical response before proceeding to local therapy. Patients achieving a pathological complete response (CR) received radiation therapy, while patients with residual disease, partial response (PR), or stable disease (NC) received debulking surgery prior to radiation therapy; in all patients, 6 additional months of chemotherapy were administered. Chemotherapy consisted of cyclophosphamide (500 mg/m2 iv) and doxorubicin (30 mg/m2 iv) on day 1; tamoxifen (40 mg/m2 orally) on days 2-6; Premarin (0.625 mg/m2 orally) every 12 hours for three doses, beginning on day 7; and methotrexate (300 mg/m2 iv) followed in 1 hour by 5-fluorouracil (500 mg/m2 iv) on day 8 and leucovorin rescue (10 mg/m2 orally) every 6 hours for six doses, beginning 24 hours after methotrexate. Fifty patients are evaluable with respect to response, time to disease progression, and survival. The rate of objective response to chemotherapy was 90%; 52% of the patients had CR, 38% had PR, and 10% had NC. The median numbers of chemotherapy cycles to achieve CR, PR, and NC were five, four, and four, respectively. Twenty-four patients with CR to chemotherapy were pathologically assessed, 22 by multiple biopsies and 2 by mastectomy. Seventy-one percent of the patients were proven to have pathological CR. All patients completing combined therapy thus far are disease free. Nine of 29 patients with stage IIIB disease have relapsed; 7 of 23 with inflammatory histology have relapsed; and 2 of 20 with stage IIIA disease have relapsed.(ABSTRACT TRUNCATED AT 250 WORDS)

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1986

Influence of definitive radiation therapy for primary breast cancer on ability to deliver adjuvant chemotherapy.

Primary radiotherapy as a means of managing stage I and II breast cancer is receiving increasing attention. In a prospectively randomized trial comparing modified radical mastectomy to lumpectomy followed by definitive radiotherapy, we evaluated whether radiotherapy has a deleterious effect on the ability to administer adjuvant doxorubicin and cyclophosphamide to patients with histologically positive axillary lymph nodes. All patients were treated with an identical regimen, and doses were escalated to the same degree until myelosuppression occurred. There were no significant differences in the amount of chemotherapy administered to either treatment group. Patients in both groups received approximately 100% of the predicted dose of doxorubicin and approximately 117% of the predicted dose of cyclophosphamide. At present, we have no evidence that there are differences in recurrence rates as a function of the quantity of drug received, although longer follow-up is required.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1986

Hormonal control of human breast cancer cell lines.

The most widely studied steroid hormone responsive cancers are those of the prostate, endometrium and mammary endothelium and the leukaemias. Steroids may in some cases be involved in tumour initiation, and they induce critical events in the malignant 'progression' of these cancers once they develop (after exposure to carcinogens, for example). This paper focuses on the role of the oestrogen receptor as a trigger of cellular growth and invasiveness and as modulator of growth factor secretion in human breast cancer. Growth factor secretion may be a common final pathway of diverse tumorigenic stimuli in a variety of cancers. The finding of external growth control mechanisms suggests possible new ways of therapeutic intervention in breast cancer.

Breast Neoplasms↗
PubMed1986

Binding characteristics and biological activity of 17 alpha-[125I]iodovinyl-11 beta-methoxyestradiol, an estrogen receptor-binding radiopharmaceutical, in human breast cancer cells (MCF-7).

17 alpha-[125I]Iodovinyl-11 beta-methoxyestradiol ([125I]MIVE2), a gamma-emitting analogue of estradiol, previously shown to bind to rat uterine estradiol receptor, was studied to determine the binding characteristics and biological activity in human breast cancer cells. In vitro determination of receptor binding by dextran-coated charcoal assays indicates that [125I]-MIVE2 binds specifically and with a high affinity to cytosolic estrogen receptors in the human breast cancer cell line, MCF-7. [3H]Estradiol binds to the receptor with approximately four times the affinity of [125I]-MIVE2 (Kd = 2.55 X 10(-9) M for [125I]MIVE2; Kd = 6.4 X 10(-10) M for [3H]estradiol). Unlabeled MIVE2 produces estrogenic effects similar to those of estradiol such as progesterone receptor induction and increases in thymidine incorporation in MCF-7 cells in culture. Cytosolic progesterone receptor levels were elevated 2.8-fold over control levels by 6 X 10(-9) M MIVE2. Stimulation of thymidine incorporation (approximately 300% above control levels) was observed after exposure to 1 X 10(-9) M MIVE2. Preliminary data show receptor-mediated uptake by the uterus in biodistribution studies in athymic nude mice given injections of [125I] MIVE2 (32-34 microCi). At 4 h, uterus:blood ratios are 20.5 and target tissue:nontarget tissue ratios are 12.9. In light of the fact that this compound can be prepared with a high specific activity, [125I]MIVE2 may have potential as a radiotracer for imaging estrogen receptor-positive breast tumors or metastatic lesions in human breast cancer patients.

Animals↗
PubMed1986

Secretion of an insulin-like growth factor-I-related protein by human breast cancer cells.

Somatomedin activity is required for proliferation of normal cells; recently somatomedin activity in the cellular environment was shown to be necessary for expression of the transformed phenotype. We demonstrate here that authentic serum-derived insulin-like growth factor-I (IGF-I) stimulates the proliferation of four human breast cancer cell lines, MCF-7, MDA-MB-231, ZR-75-1, and Hs578T in serum-free monolayer culture and that each of these lines produces and secretes an IGF-I-related growth factor. The two highly tumorigenic estrogen-independent cell lines, MDA-MB-231 and Hs578T, produced 2- to 10-fold more IGF-I than did two estrogen responsive cell lines, MCF-7 and ZR-75-1, which are not tumorigenic in the absence of estrogen. These breast cancer cells also secrete a Mr 50,000 binding activity which partially obscured detection of IGF-I by radioimmunoassay. Acid-ethanol extraction allowed dissociation of the high molecular weight complex; whereupon, fully immunoreactive IGF-I comigrated on acid gel exclusion chromatography with authentic human serum-derived IGF-I. Radioimmunoassay displacement curves for breast cancer cell line-derived IGF-I were parallel to those for authentic IGF-I. Northern blot analysis of mRNA from four breast cancer cell lines demonstrated specific hybridization with a human IGF-I probe corresponding to one of the two major transcripts seen in human liver mRNA. These data suggest that breast cancer cell line-derived IGF-I is similar to liver-synthesized, serum-derived IGF-I.

Breast Neoplasms↗
PubMed1986

Use of two MCF-7 cell variants to evaluate the growth regulatory potential of estrogen-induced products.

Two variants of the human estrogen-responsive breast cancer cell line MCF-7, were utilized to study the expression of an estrogen-induced gene, pS2, and an estrogen-induced Mr 52,000 protein. One variant cell line, I13, is growth inhibited after chronic exposure to estrogen. Both the pS2 gene product and the Mr 52,000 protein were produced at maximal levels at a time when I13 growth was inhibited by estrogen. The variant cell line, LY2, selected for its resistance to the growth-inhibitory effects of the antiestrogen, LY117018, grew normally in the presence of this drug, although both pS2 expression and Mr 52,000 protein production were inhibited. These results confirm that the pS2 gene and Mr 52,000 protein are estrogen-regulated elements, but the lack of correlation between their activities and variant cell growth suggests that they are not major autocrine growth-stimulatory agents.

Breast Neoplasms↗
PubMed1985

Transfection of v-rasH DNA into MCF-7 human breast cancer cells bypasses dependence on estrogen for tumorigenicity.

The natural history of estrogen-responsive breast cancers often involves a phenotypic change to an estrogen-unresponsive, more aggressive tumor. The human breast cancer cell line, MCF-7, which requires estradiol for tumor formation in vivo and shows growth stimulation in response to estradiol in vitro, is a model for hormone-responsive tumors. The v-rasH onc gene was transfected into MCF-7 cells. The cloned MCF-7ras transfectants, which expressed the v-rasH messenger RNA and v-rasH p21 protein (21,000 daltons), were characterized. In contrast to the parental cell line, MCF-7ras cells no longer responded to exogenous estrogen in culture and their growth was minimally inhibited by exogenous antiestrogens. When tested in the nude mouse, the MCF-7ras cells were fully tumorigenic in the absence of estrogen supplementation. Thus, cells acquiring an activated onc gene can bypass the hormonal regulatory signals that trigger the neoplastic growth of a human breast cancer cell line.

Animals↗