Autocrine growth hormone (hGH) and chemotherapeutic drug resistance in mammary carcinoma cells 3

1 Chapter Introduction Breast cancer is by far the most frequent cancer in women and the leading cause of cancer related death in women Breast cancer has been a major fatal disease in westernized countries, but it is becoming a prominent one also in several developing countries Numerous factors have been shown to be associated with increased breast cancer risks Understanding those factors might contribute to novel adjunct therapeutic approaches in the treatment of breast cancer A large body of evidence has indicated an association between hormones and breast cancer risk In addition to estrogen, growth hormone has recently been emerging as one hormone involved in breast cancer 1.1 Hormones and breast cancer risk That hormones influence risk of breast cancer has been known for decades Women who have had bilateral oophorectomy early in life are at markedly reduced risk of subsequently developing breast cancer; the earlier oophorectomy is done, the greater the reduction Early age at menarche (11 years or less) and late age at natural menopause (55 or older) are associated with increased risk Late age at full-term pregnancy (30 or more) increases risk compared to an early age (less than 20) Nulliparity increases risk and high parity decreases risk, at least after age 50 (Kelsey et al 1993; Rosner et al 1994) Obesity, which increases risk in postmenopausal women, is thought to operate through a hormonal mechanism (Sellers et al 1992) Obese women metabolize androstenedione, produced in the adrenal cortex, to oestrogen in adipose cells The higher levels of serum oestrone in obese as compared to nonobese postmenopausal women may account for the excess breast cancer risk (Cauley et al 1989) In premenopausal women, breast feeding, if continued for many months or years, appears to reduce risk A multinational study conducted by the World Health Organization, suggested that oral contraceptives are associated with increased risk for breast cancer incidence before the age of 40-45 (Thomas and Noonan 1990) Many studies have been done to elucidate the association of hormones and breast cancer risk Associations have been demonstrated between estrogen, prolactin, growth hormone (GH) and insulin-like growth factor-1 (IGF-1) with breast cancer In this study, we focused on the role of GH in breast cancer 1.2 Growth hormone (GH) and breast cancer GH is one of the mammotrophic hormones involved in the development of the breast hGH mRNA identical to pituitary hGH mRNA is also expressed by normal mammary tissue and by benign and malignant human mammary tumors and the immunoreactive hGH is restricted to epithelial cells (Mol et al 1995a) A recent study showed increased expression of the hGH gene in proliferative disorders of the mammary gland (Raccurt et al 2002) The pituitary and mammary gland GH gene transcripts originate from the same transcription start site but are regulated differentially, since mammary gland GH gene transcription does not require Pit-1 (Lantinga-van Leeuwen et al 1999) GH receptor mRNA and protein have also been detected in human mammary gland epithelia (Sobrier et al 1993) Both endocrine GH and autocrine/paracrine-produced GH possess the capacity to exert a direct effect on the development and differentiation of mammary epithelia in vitro (Plaut et al 1993) and in vivo (Feldman et al 1993) All these findings indicate the possible involvement of hGH in mammary carcinoma To further elucidate the effect of autocrine hGH in mammary carcinoma cell, a new in vitro cell culture model was developed (Kaulsay et al 1999) The hGH gene or a translation-deficient hGH gene were stably transfected into MCF-7 cells, a human mammary carcinoma cell line (Kaulsay et al 1999) The autocrine hGH producing cells display a marked insulin-like growth factor-1-independent increase in cell number in both serum-free and serum-containing conditions as well as a specific increase in STAT5-mediated transcription (Kaulsay et al 1999) Also, autocrine hGH production resulted in enhancement of the rate of mammary carcinoma cell spreading on a collagen substrate In a later study, Kaulsay demonstrated that the increase in mammary carcinoma cell number was not only a result of increased mitogenesis but also a decrease in apoptosis by autocrine hGH (Kaulsay et al 2000) This antiapoptotic effect of autocrine hGH might explain the phenomenon that metastatic mammary carcinoma, which show the highest expression of hGH, is more resistant to chemotherapy Thus, understanding this protective effect of autocrine hGH in mammary carcinoma cells may contribute to novel adjunct therapeutic approaches to the treatment of mammary cancer 1.3 Possible mechanisms involved in resistance to breast cancer treatment It has been frequently noticed that chemotherapy is efficient in early stages of breast cancer, whereas advanced tumors are usually resistant to the same treatments The molecular basis for this resistance is not understood Many chemotherapeutic drugs are DNA or cytoskeleton damaging drugs that show some specificity towards dividing cells In recent studies, increased cellular oxidative level was shown to be a key effector of cell death induced by chemotherapeutic drugs (Wen et al 2002) However, in advanced tumors the cellular oxidative level is down regulated and, consequently, death signaling is suppressed This difference in the level of antioxidant enzymes in tumors may underlie the difference in responsiveness to chemotherapy (Akman et al 1990) Increased expression of antioxidant enzymes has been documented in a wide variety of malignant tumors including breast cancer (di Ilio et al 1985; Iscan et al 2002) and higher expression level of antioxidant enzymes was shown to be associated with large, poorly differentiated breast tumors (Thomas et al 1997) Understanding these mechanisms of chemoresistance may help us find new effective therapeutic approaches for the treatment of chemoresistant breast cancer patients 1.4 Direction of the study As stated above, both the clinical and cell model data suggest an association between autocrine hGH and breast cancer Autocrine hGH production by mammary carcinoma cells could impact on breast cancer cell behavior and consequently cancer prognosis An increased antioxidant enzyme level has been shown to contribute to chemoresistance of advanced cancer cells and this increased level been documented in a wide variety of malignant tumors including breast cancer (di Ilio et al 1985; Iscan et al 2002) and is associated with large, poorly differentiated breast tumors (Thomas et al 1997) It is clear that more studies need to be done to further elucidate the possible relationship between autocrine hGH and antioxidant enzymes level in breast cancer cells The first line defense antioxidant enzymes are superoxide dismutase (SOD), glutathione peroxidase (GPX), glutamylcystein synthetase (GCS) and catalase Among them, catalase is the most potent enzyme regulating oxidative stress level by converting H2O2 to H2O and O2 in peroxisomes A higher expression level of catalase has been found in tumor tissues compared with normal tissues (Ripple et al 1997), and this has been correlated with mammary tumor malignancy grade and prognosis (Thomas et al 1997) However, to date the mechanisms responsible for the regulation of catalase are largely unknown Therefore, further work is necessary to elucidate the pathways and molecules involved in the regulation of catalase and explore the possible signaling pathways used by autocrine hGH to promote chemoresistance and influence the outcome of cancer treatment 1.5 Objectives The purpose of the study was to analyze the impact of autocrine hGH on chemotherapy resistance, concentrating especially in further characterization of the role of autocrine hGH on antioxidant enzymes, especially catalase, in mammary carcinoma cells, but also exploring other mechanisms of chemoresistance in relation to autocrine hGH My work is therefore mainly focused on exploring the signaling pathways by which autocrine hGH regulates catalase level and its consequent influence on the responsiveness of mammary neoplasia to chemotherapy A detailed description of the purpose of my study is listed below: I Analysis of the impact of autocrine hGH on chemotherapy resistance using the MCF-7 cell model a Analyzing the effect of autocrine hGH on cell death induced by chemotherapeutic drugs in mammary carcinoma cells b Analyzing the effect of autocrine hGH on cell death induced by other oxidative stress inducers in mammary carcinoma cells II Characterization of the role of autocrine hGH on antioxidant enzymes in mammary carcinoma cells might contribute to the chemoresistance effect of autocrine hGH in mammary carcinoma cells a Analyzing the effect of autocrine hGH on antioxidant enzymes: catalase, SOD, GPX, GCS at mRNA and protein level by RT-PCR and Western Blot in mammary carcinoma cells respectively b Analyzing the contribution of induced catalase expression by autocrine hGH to the protective effect of autocrine hGH in mammary carcinoma cells using catalase-specific inhibitor and forced expression of catalase by its expression vector c Exploration of the signaling pathways by which autocrine hGH regulate catalase level • Analyzing effect of autocrine hGH on a 4.5Kb catalase gene promoter in mammary carcinoma cells • Using different pathway inhibitors to identify the main pathway through which catalase level is regulated by autocrine hGH in mammary carcinoma cells • Confirming the importance of this pathway involved in the protective effect of autocrine hGH III Characterization of the role of autocrine hGH on apoptotic proteins in mammary carcinoma cells might contribute to the chemoresistance effect of autocrine hGH in mammary carcinoma cells a Analyzing the effect of autocrine hGH on apoptotic proteins: Bcl-2, Bclxl, Bak, Bax, p53 at protein level by Western Blot in mammary carcinoma cells b Exploring the effect of autocrine hGH on Bcl-xl promoter activity c Exploring the effect of autocrine hGH on Bcl-2 phosphorylation status IV Characterization of the role of autocrine hGH on telomerase activity in mammary carcinoma cells which might contribute to the chemoresistance effect of autocrine hGH in mammary carcinoma cells a Analyzing the effect of autocrine hGH on telomerase activity b Analyzing the effect of autocrine hGH on telomerase associated proteins at mRNA and protein level by RT-PCR and Western Blot in mammary carcinoma cells respectively c Exploring the regulation mechanism of autocrine hGH on hTERT mRNA by promoter reporter assay Ongoing research of growth hormone receptor-specific antagonists holds promise at blocking the actions of hGH at the endocrine and autocrine levels within the breast Analyzing the relationship and signalling cascades between autocrine hGH and catalase in mammary carcinoma cells may answer the question of differences in chemotherapy response of breast cancer patients Thus, it might yield a novel adjuvant therapeutic approach for the treatment of chemoresistant breast cancer patients Chapter Literature review 2.1 Growth hormone 2.1.1 Growth hormone structure Human growth hormone (hGH) is a 191 amino acid single chain polypeptide with a molecular weight of 22kDa It consists of four antiparallel alpha helices (AbdelMeguid et al 1987)with two interchain disulfide bonds (Li and Dixon 1971; Niall 1971) and an unsubstituted amino terminus (Wallis 1992) Two human GH genes, hGH-N and hGH-V have been identified (MacLeod et al 1991) In man, 22kDa hGH is expressed in the pituitary from the hGH-N gene (located on chromosome 10), which contains exons The 22kDa from of GH is the most abundant one and contributes to 70-75% of circulating GH (Wallis 1992) The hGH-N undergoes alternate splicing at the 3’ acceptor site in exon (DeNoto et al 1981) to produce a 20kDa GH variant by a deletion of amino acids 32-46 (Lewis et al 1978), which constitutes up to 15% of secreted GH (DeNoto et al 1981) Western blot analysis of human serum has demonstrated different molecular weight forms of GH at 27 KDa, 22kDa, 20kDa and 17kDa (Sinha and Jacobsen 1994; Warner et al 1993) The 17kDa hGH consists of amino acids 44-191 (reportedly diabetogenic fragment of hGH) and is altered by the physiologic state of the individual (Sinha and Jacobsen 1994) The hGH-V variant GH (Wallis 1992) is synthesized by the placenta and is encoded by a 10 separate gene (Frankenne et al 1987) Human GH and hGH-V differ by only 13 of a total of 191 amino acids Growth hormone (GH) belongs to a family of polypeptide hormones, which includes prolactin (PRL), placental lactogen (PL; somatomammotropin), and proliferin (Linzer and Nathans 1985; Nicoll et al 1986; Wallis 1992) Human GH shares the greatest sequence homology with human PL, more than with porcine GH (73%), bovine GH, equine GH and rat GH (each approximately 65%) (Wallis et al 1978), or the PRL family (approximately 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