Oral Contraceptives and Breast Cancer (1991) / Chapter Skim
Currently Skimming:
3. Biology: Information Needs and Data Gaps
3. Biology: Information Needs and Data Gaps
Pages 35-54
The Chapter Skim interface presents what we've algorithmically identified as the most significant single chunk of text within every page in the chapter.
Select key terms on the right to highlight them within pages of the chapter.
From page 35... ...
The synthetic hormones contained in oral contraceptives simulate the natural steroid hormones secreted by the ovaries and placenta.
|
From page 36... ...
Growth factors can act as local growth regulators and can inhibit or stimulate mitogenesis of epithelial or stromal cells; they can also stimulate angiogenesis and influence cell transformation and immortalization. In culture, normal or malignant breast tissue can secrete transforming growth factors (TGF-oc)
|
From page 37... ...
In a number of tissues, including breast epithelium, it has been observed in vitro that normal epithelial function, such as secretion or differentiation, does not take place unless a normal extracellular matrix is present. Many hormone effects on target cells are mediated by actions of ECM protein secretions, or by secretion of growth factors locally.
|
From page 38... ...
are and will remain the central source of information concerning the link, if any, between oral contraceptives and breast cancer. Rapid advances in molecular endocrinology and in the biochemistry and biology of growth factors and steroid and peptide hormones now permit scientists to gain some insight into the biological links between breast neoplasia and oral contraceptives.
|
From page 39... ...
The 17Oc-ethinyl estrogens in oral contraceptives are metabolized primarily by the 2-hydroxylative route with minimal 16OC hydroxylation. The difference in metabolic pathways between the natural and the synthetic estrogens could have important biological consequences and may be relevant to the occurrence of breast cancer.
|
From page 40... ...
? · How relevant are ECM proteins and growth factors to the etiology of breast cancer?
|
From page 41... ...
In turn, ascribing a possible role of oral contraceptives in such transformation will not be readily proven. Timing During the process of development, there are critical periods when a given target tissue can be altered irreversibly by a signal for example, by a hormone.
|
From page 42... ...
Efforts to determine the effect of oral contraceptives on the risk of developing breast cancer should probably focus on the effect of these agents on normal breast tissue. Cystic conditions- in some instances, gross cystic disease- are common during the reproductive years, and although such tissue might be considered abnormal, recent studies do not reveal an increase in breast cancer in such patients.
|
From page 43... ...
The important question concerning oral contraceptives is their effect on normal breast epithelium, as breast cancer has already been studied intensively. Consequently, the committee emphasizes this necessary concentration on the largest gap in our present knowledge: the transformation of benign to malignant epithelium.
|
From page 44... ...
If the effects of estrogens and antiestrogens on mitogenesis and various aspects of breast cell intracellular metabolic pathways are mediated by secondary factors like locally secreted growth factors and extracellular matrix protein production, then any autonomous constitutive secretion of these factors could mediate transformation of an initially estrogen-dependent tumor into an estrogen-independent tumor. This conversion might result from the action of an oncogene.
|
From page 45... ...
G-proteins normally act by transmitting proliferative signals initiated by extracellular hormones and growth factors. They bind guanine nucleotides and mediate signal transduction through effecters such as adenylate cyclase.
|
From page 46... ...
Yet abnormal cell growth may also result from overexpression of normal growth factor receptors. Three related tyrosine kinase transmembrane proteins are expressed at increased levels in breast cancer: the epidermal growth factor, or EGF, receptor, the receptor-like product of the erbB-2 oncogene, and the product of a recently described gene, erbB-3.
|
From page 47... ...
ins-1 related genes are not amplified, translocated, or even expressed in human breast cancer. In contrast, the ins-2 gene is amplified in 15 percent of breast cancers.
|
From page 48... ...
. Thus, it is possible that species-specific effects of exogenous steroids such as oral contraceptives will be of primary importance with regard to induction of mammary cancers.
|
From page 49... ...
This readily available source of estrogen receptor-positive cells permitted extensive characterization of the mechanisms by which estrogen receptors control gene expression (for a review, see Dickson and Lippman, 1987~. Studies using these cell lines have also been directly useful in the clinic because the cell lines support more rapid, detailed characterization of potential estrogen receptor inhibitors, such as tamoxifen.
|
From page 50... ...
it Short-term Culture of Normal Mammary Epithelium Studies on breast cancer cell lines cannot address many of the relevant questions related to the potential link of oral contraceptives and breast cancer. Therefore, it will be critical to develop in vitro model systems that use normal human mammary epithelium.
|
From page 51... ...
This technique also isolates capillary endothelium, but the endothelial cells do not grow in the media formulations developed for the epithelium. Mammary epithelial cells proliferate in a variety of culture conditions, including collagen coating of the culture surface, the presence of various growth factors such as epidermal growth factor and cholera toxin, reduced calcium concentrations, or conditioned media from specific cell lines.
|
From page 52... ...
Only then will it be possible to explore in vitro the critical research questions that relate to the actions of oral contraceptives on normal breast tissue function. Organ Culture In vitro cell culture has been invaluable for studying the effects of various stimuli directly on synthesis and secretion of many cell products.
|
From page 53... ...
These culture conditions may simulate the intact mammary tissue better than in vitro conditions. Furthermore, given the mouse's low endogenous estrogen levels, this model may be valuable for studying the effects of cyclic administration of various oral contraceptives on normal mammary epithelium.
|
From page 54... ...
What are the effects of the progestin component of oral contraceptives in modulating estrogen action? Do the inherent androgenic or antiestrogenic properties of different oral contraceptive formulations affect normal breast tissue response?
|
Key Terms
This material may be derived from roughly machine-read images, and so is provided only to facilitate research.
More
information on Chapter Skim is available.