Growth Hormone and Insulin-Like Growth Factor-I in the Transition from Normal Mammary Development to Preneoplastic Mammary Lesions (vol 30, pg 51, 2009)

Neuroendocrine Unit, Department of Medicine, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA.
Endocrine reviews (Impact Factor: 19.36). 02/2009; 30(1):51-74. DOI: 10.1210/er.2008-0022
Source: PubMed

ABSTRACT Adult female mammary development starts at puberty and is controlled by tightly regulated cross-talk between a group of hormones and growth factors. Although estrogen is the initial driving force and is joined by luteal phase progesterone, both of these hormones require GH-induced IGF-I in the mammary gland in order to act. The same group of hormones, when experimentally perturbed, can lead to development of hyperplastic lesions and increase the chances, or be precursors, of mammary carcinoma. For example, systemic administration of GH or IGF-I causes mammary hyperplasia, and overproduction of IGF-I in transgenic animals can cause the development of usual or atypical hyperplasias and sometimes carcinoma. Although studies have clearly demonstrated the transforming potential of both GH and IGF-I receptor in cell culture and in animals, debate remains as to whether their main role is actually instructive or permissive in progression to cancer in vivo. Genetic imprinting has been shown to occur in precursor lesions as early as atypical hyperplasia in women. Thus, the concept of progression from normal development to cancer through precursor lesions sensitive to hormones and growth factors discussed above is gaining support in humans as well as in animal models. Indeed, elevation of estrogen receptor, GH, IGF-I, and IGF-I receptor during progression suggests a role for these pathways in this process. New agents targeting the GH/IGF-I axis may provide a novel means to block formation and progression of precursor lesions to overt carcinoma. A novel somatostatin analog has recently been shown to prevent mammary development in rats via targeted IGF-I action inhibition at the mammary gland. Similarly, pegvisomant, a GH antagonist, and other IGF-I antagonists such as IGF binding proteins 1 and 5 also block mammary gland development. It is, therefore, possible that inhibition of IGF-I action, or perhaps GH, in the mammary gland may eventually play a role in breast cancer chemoprevention by preventing actions of both estrogen and progesterone, especially in women at extremely high risk for developing breast cancer such as BRCA gene 1 or 2 mutations.

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    • "Experimental models involving carcinogen challenge have been used widely to demon strate that hormones and growth factors influence MG develop ment, differentiation, and carcino genesis; these models could read­ ily be extended to evaluate increased cancer risk from early life environmental exposures. These models have been used, for example, to investigate potential chemo preventive agents that accelerate MG differentiation (e.g., by mimicking pregnancy hormones) and decrease tumor susceptibility (Cotroneo et al. 2002; Kleinberg et al. 2009; Russo and Russo 1996 "
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    ABSTRACT: Perturbations in mammary gland (MG) development may increase risk for later adverse effects, including lactation impairment, gynecomastia (in males), and breast cancer. Animal studies indicate that exposure to hormonally active agents leads to this type of developmental effect and related later life susceptibilities. In this review we describe current science, public health issues, and research recommendations for evaluating MG development. The Mammary Gland Evaluation and Risk Assessment Workshop was convened in Oakland, California, USA, 16-17 November 2009, to integrate the expertise and perspectives of scientists, risk assessors, and public health advocates. Interviews were conducted with 18 experts, and seven laboratories conducted an MG slide evaluation exercise. Workshop participants discussed effects of gestational and early life exposures to hormonally active agents on MG development, the relationship of these developmental effects to lactation and cancer, the relative sensitivity of MG and other developmental end points, the relevance of animal models to humans, and methods for evaluating MG effects. Normal MG development and MG carcinogenesis demonstrate temporal, morphological, and mechanistic similarities among test animal species and humans. Diverse chemicals, including many not considered primarily estrogenic, alter MG development in rodents. Inconsistent reporting methods hinder comparison across studies, and relationships between altered development and effects on lactation or carcinogenesis are still being defined. In some studies, altered MG development is the most sensitive endocrine end point. Early life environmental exposures can alter MG development, disrupt lactation, and increase susceptibility to breast cancer. Assessment of MG development should be incorporated in chemical test guidelines and risk assessment.
    Environmental Health Perspectives 06/2011; 119(8):1053-61. DOI:10.1289/ehp.1002864 · 7.03 Impact Factor
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    • "In addition to the important role of the IGF system in normal mammary development, it has been proposed that overproduction of GH or IGF-I can also cause the development of atypical hyperplasias or even carcinoma (Kleinberg et al. 2009). While it is not understood how early full-term pregnancy can provide natural protection against breast cancer, serum GH levels, and downstream signaling activity were shown to be decreased in parous animals compared to virgins (Dearth et al. 2010). "
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    ABSTRACT: Results from clinical trials have demonstrated that it is possible to prevent estrogen-responsive breast cancers by targeting the estrogen receptor with selective estrogen receptor modulators (SERMs) (tamoxifen, raloxifene, or lasofoxifene) or with aromatase inhibitors (AIs) (anastrozole, letrozole, or exemestene). Results from breast cancer treatment trials suggest that aromatase inhibitors may be even more effective in preventing breast cancer than SERMs. However, while SERMs and aromatase inhibitors do prevent the development of many ER-positive breast cancers, these drugs do not prevent ER-negative breast cancer. These results show that new approaches are needed for the prevention of this aggressive form of breast cancer. Our laboratory and clinical efforts have been focused on identifying critical molecular pathways in breast cells that can be targeted for the prevention of ER-negative breast cancer. Our preclinical studies have demonstrated that other nuclear receptors, such as RXR receptors, vitamin D receptors, as well as others are critical for the growth of ER-negative breast cells and for the transformation of these cells into ER-negative cancers. Other studies show that growth factor pathways including those activated by EGFR, Her2, and IGFR, which are activated in many ER-negative breast cancers, can be targeted for the prevention of ER-negative breast cancer in mice. Clinical studies have also shown that PARP inhibitors are effective for the treatment of breast cancers arising in BRCA-1 or -2 mutation carriers, suggesting that targeting PARP may also be useful for the prevention of breast cancers arising in these high-risk individuals. Most recently, we have demonstrated that ER-negative breast cancers can be subdivided into four distinct groups based on the kinases that they express. These groups include ER-negative/Her-2-positive groups (the MAPK and immunomodulatory groups) and ER-negative/Her2-negative groups (the S6K and the cell cycle checkpoint groups). These groups of ER-negative breast cancers can be targeted with kinase inhibitors specific for each subgroup. These preclinical studies have supported the development of several clinical trials testing targeted agents for the prevention of breast cancer. The results of a completed Phase II cancer prevention trial using the RXR ligand bexarotene in women at high risk of breast cancer will be reviewed, and the current status of an ongoing Phase II trial using the EGFR and Her2 kinase inhibitor lapatinib for the treatment of women with DCIS breast cancer will be presented. It is anticipated that in the future these molecularly targeted drugs will be combined with hormonal agents such as SERMs or aromatase inhibitors to prevent all forms of breast cancer.
    Recent results in cancer research. Fortschritte der Krebsforschung. Progrès dans les recherches sur le cancer 01/2011; 188:147-62. DOI:10.1007/978-3-642-10858-7_13
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    • "Although biological mechanisms in humans remain to be elucidated, Kleinberg and Ruan have demonstrated that these two hormones also play a key role in mammary gland development in rodents by increasing breast cell proliferation (Kleinberg and Ruan 2008). Furthermore, experimental evidence from the same laboratory has demonstrated that GH and IGF-I are associated with the development of preneoplastic mammary lesions when experimentally perturbed (Kleinberg et al. 2009). These observations are consistent with the findings of Ahlgren et al. that factors that influence growth are independent risk factors for breast cancer (Ahlgren et al. 2004). "
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    ABSTRACT: It seems paradoxical that both increased height and earlier age at menarche (which predicts for shorter stature) are both associated with increased breast cancer risk. Retrospective data from a parental cohort coupled with prospective interviews with and anthropometric measurements from their daughters were used. Multivariable linear regression analyses were conducted using mixed regression models to account for same-family participants. Controlling for birth weight, maternal height, and birth cohort, and analyzed as a group, a 1-year increase in the age at menarche predicted an increase in standing height, leg length, and trunk height of 0.76, 0.41, and 0.35 cm, respectively. However, when stratifying by birth year (prior to 1966 vs 1966 or after), these relationships were true only for those born prior to 1966. Given the height-breast cancer risk association, the emerging evidence linking breast cell proliferation to hormones associated with growth, and the finding in this study that the relationship between age at menarche and adult height no longer exists for women born in 1966 or later, it is possible that the long-established relationship between age at menarche and breast cancer risk may also no longer exist.
    Annals of Human Biology 02/2010; 37(1):76-85. DOI:10.3109/03014460903213845 · 1.15 Impact Factor
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