Temporal factors alter effects of social housing conditions on responses to chemotherapy and hormone levels in a Shionogi mammary tumor model.

OBJECTIVE: To identify possible hormonal factors involved in the differential responses to chemotherapy observed in our tumor model, we investigated if the timing among tumor cell injection, rehousing, and chemotherapy administration differentially affects levels of corticosterone (CORT), growth hormone (GH), and testosterone and tumor and host responses to chemotherapy. METHODS: Mice were reared either individually (I) or in groups (G). At 2 to 4 months, mice were injected with tumor cells and retained in their original housing conditions or rehoused into different experimental groups (GG, IG, II, GI) either immediately (experiment 1) or 14 days later (experiment 2); chemotherapy was administered when tumors weighed approximately 0.8 g. RESULTS: In experiment 1, IG and GG mice had better responses to chemotherapy than GI mice. Chemotherapy increased CORT levels in II mice and decreased GH levels in GI mice compared with those of their drug vehicle-treated counterparts. Under the temporal conditions of experiment 2, IG and GG mice lost the advantage seen in experiment 1 in terms of tumor and host responses to chemotherapy. Before chemotherapy administration, CORT levels in IG mice and GH levels in GI mice were higher than those in mice in all other housing conditions. At 1 day after chemotherapy, CORT levels were higher for chemotherapy-treated than for drug vehicle-treated IG mice, and at 5 days post chemotherapy, GH levels were higher in GI than in IG mice. CONCLUSIONS: Temporal relationships among tumor cell injection, rehousing, and chemotherapy administration critically influence responses to chemotherapy; these effects may be mediated, in part, by alterations in hormone levels.

Mitogenic properties of insulin-like growth factors I and II, insulin-like growth factor binding protein-3 and epidermal growth factor on human breast stromal cells in primary culture.

Insulin-like growth factors I and II (IGF-I and IGF-II) are growth factors implicated in both normal mammary gland development and breast cancer. We have previously reported on the effects of components of the IGF system on breast epithelial cells. Since data suggests that stromal-epithelial interactions play a crucial role in breast cancer, we have now investigated the mitogenic properties of IGF-I, IGF-II, insulin-like growth factor binding protein-3 (IGFBP-3) and epidermal growth factor (EGF) on human breast stromal cells in primary culture. We show that, under serum-free conditions, stromal cells are stimulated to grow in response to IGF-I and IGF-II in a dose-dependent manner. IGF-I and EGF, a potent stimulator of human breast epithelial cell growth in primary culture and also associated with breast cancer, appear to stimulate stromal cell growth in a synergistic manner. IGFBP-3 does not inhibit the stimulation of growth by IGF-I, or IGF-I plus EGF. However, IGFBP-3 does inhibit the stimulation of growth by IGF-II. In contrast to our previous results with human breast epithelial cells, IGFBP-3 does not have an IGF-independent inhibitory effect on stromal cell growth. This study is the first to address the effects of IGF-I, IGF-II and IGFBP-3 alone and in combination with EGF on human breast stromal cell growth in primary culture. Characterizing the role of the IGF system in both normal breast epithelial cells and stromal cells will aid in our understanding of the mechanisms behind the role of the IGF system in breast cancer.

Necrosis and hypoxia in invasive breast carcinoma.

To investigate the relation between necrosis and hypoxia in breast cancer we examined the expression of hypoxia-associated markers HIF1, CA IX and GLUT1 by immunohistochemistry in 97 invasive ductal carcinomas. This selected series comprised 48 tumors with extensive necrosis and 49 control tumors without necrosis. Over 90% of necrotic and 30% of non-necrotic tumors expressed at least one hypoxia marker. We also observed expression of hypoxia associated markers in tumor stroma. Examination of primary human breast fibroblasts in vitro confirmed that CA IX mRNA and protein can be induced by hypoxia. Survival analysis of 53 cases found that the subset of tumors with stromal hypoxia exhibit better prognosis (p=0.027). Our results indicate that necrosis is often accompanied by hypoxia but that hypoxia without necrosis may also be a frequent occurrence. The use of several hypoxia markers may identify a continuum of hypoxia in tumors, which can be sub-classified by different co-expression patterns. We conclude that stromal and epithelial hypoxia may have different biological backgrounds and that stromal hypoxia may affect survival.

Mitogenic properties of insulin-like growth factors I and II, insulin-like growth factor binding protein-3 and epidermal growth factor on human breast epithelial cells in primary culture.

Insulin-like growth factor-I (IGF-I) and insulin-like growth factor-II (IGF-II) are growth factors implicated in mammary gland development and are believed to be involved in breast cancer. However, the interactions between components of the IGF system and breast epithelial cells, which give rise to breast cancer, are not well understood. We have investigated the mitogenic properties of IGF-I, IGF-II, IGF binding protein-3 (IGFBP-3) and epidermal growth factor (EGF) on human breast epithelial cells (HBEC) in primary culture. We show that, under serum-free conditions, HBEC are stimulated to grow in response to IGF-I and IGF-II in a dose-dependent manner. IGF-I and EGF, a potent stimulator of HBEC growth in primary culture and also associated with breast cancer, appear to stimulate HBEC in a synergistic manner. IGFBP-3 inhibits the stimulation by IGF-I, IGF-II and IGF-I plus EGE In addition, it appears that IGFBP-3 has an inhibitory effect on HBEC growth that is IGF-independent. This study is the first to address the effects of IGF-I, IGF-II and IGFBP-3 alone and in combination with EGF on HBEC growth in primary culture. Characterizing the role of the IGF system in normal breast biology is significant because the system has been implicated in breast cancer and a number of the anti-estrogens used in treatment are believed to function through the IGF system.