[en] The mammary gland undergoes morphogenesis through the entire reproductive life of mammals. In mice, ductal outgrowth from the nipple across the fat pad results in an intricate, well spaced ductal tree that further ramifies and develops alveolar structures during pregnancy. Ductal morphogenesis is regulated by the concerted action of circulating steroid and polypeptide hormones, and local epithelial-mesenchymal inductive signals. Transforming growth factor (TGF)-β_1_-_3 and hepatocyte growth factor (HGF)/scatter factor (SF) are important components of this latter signaling pathway. TGF-β_1 and TGF-β_3 have roles in both promotion and inhibition of branching morphogenesis that are dependent on concentration and context. HGF/SF promotes ductal outgrowth and tubule formation in the mammary gland. These data suggest that these two growth factors have complementary roles in promoting mammary ductal morphogenesis and in maintaining ductal spacing. In addition, TGF-β_3 triggers apoptosis in the alveolar epithelia, which is a necessary component of mammary gland involution and return of the ductal structure to a virgin-like state after lactation

[en] Introduction: Novel therapeutic modalities are needed for breast cancer patients in whom standard treatments are not effective. Mammary gland sodium/iodide symporter has been identified as a molecular target in breast cancers in humans and in some transgenic mouse models. We report the results of a therapy study with ¹³¹I^- and ¹⁸⁸ReO₄^- of breast cancer in polyoma middle T oncoprotein (PyMT) transgenic mice endogenously expressing the Na⁺/I^- symporter (NIS). Methods: PyMT mice (12-13 weeks old) with one palpable tumor of 0.5-0.8 cm in diameter were used. For the therapy studies, PyMT mice were (1) treated with two intraperitoneal injections of 1.5 mCi of ¹⁸⁸ReO₄^- 1 week apart, (2) pretreated for 1 week with 5 μg of triiodothyronine (T3) followed by two intraperitoneal injections of 1.5 mCi of ¹³¹I^- 1 week apart or (3) left untreated. The tumor and normal organ uptakes were assessed by scintigraphic imaging. The thyroid function of treated and control animals was evaluated at the completion of the study by measuring the T3/thyroxine (T4) ratio in their blood. Results: There was significant uptake of ¹³¹I^- and ¹⁸⁸ReO₄^- in the primary palpable tumors as well as in nonpalpable tumors, stomachs and thyroids. The tumor uptake after the second injection was 10 times lower in comparison with the first injection. Tumor growth was significantly inhibited in both the ¹³¹I^- and ¹⁸⁸ReO₄^- groups in comparison with the control group, and tumors in the ¹⁸⁸ReO₄^- group increased in size significantly less than in the ¹³¹I^- group. The T3/T4 ratios were calculated to be 27 and 25 for the control group and the ¹⁸⁸ReO₄^- group, respectively; for ¹³¹I^-, both the T3 and T4 levels were below detection limit, demonstrating much less effect on the thyroids of treatment with ¹⁸⁸ReO₄^- than with ¹³¹I^-. Conclusions: These results prove that NIS expression in breast tumors in animal models allows specific, efficient and safe treatment with a variety of radionuclides transported by NIS

[en] Novel approaches are needed for breast cancer patients in whom standard therapy is not effective. 2-Deoxy-2-["1"8F]fluoro-D-glucose ("1"8F-FDG) was evaluated as a potential radiomolecular therapy agent in breast cancer animal models and, retrospectively, in patients with metastatic breast cancer. Polyoma middle T antigen (PyMT) and mouse mammary tumor virus-NeuT transgenic mice with tumors 0.5–1 cm in diameter were imaged with "1"8F-FDG, and tumor to liver ratios (TLRs) were calculated. The radiotoxicity of "1"8F-FDG administration was determined in healthy mice. PyMT mice with small (0.15–0.17 cm) and large (more than 1 cm) tumors were treated with 2–4 mCi of "1"8F-FDG, and control C3H/B6 mice with 3 mCi of "1"8F-FDG. At 10 days after treatment the tumors and control mammary glands were analyzed for the presence of apoptotic and necrotic cells. Five patients with breast cancer and metastatic disease were evaluated and standardized uptake values (SUVs) in tumors, maximum tolerated dose, and the doses to the tumor were calculated. Doses up to 5 mCi proved to be non-radiotoxic to normal organs. The "1"8F-FDG uptake in mouse tumors showed an average TLR of 1.6. The treatment of mice resulted in apoptotic cell death in the small tumors. Cell death through the necrotic pathway was seen in large tumors, and was accompanied by tumor fragmentation and infiltration with leukocytes. Normal mammary tissues were not damaged. A human "1"8F-FDG dose delivering 200 rad to the red marrow (less than 5% damage) was calculated to be 4.76 Ci for a 70 kg woman, and the dose to the tumors was calculated to be 220, 1100 and 2200 rad for SUVs of 1, 5 and 10, respectively. We have shown that positrons delivered by "1"8F-FDG to mammary tumors have a tumoricidal effect on cancer cells. The study of breast cancer patients suggests that the tumor and normal organ dosimetry of "1"8F-FDG makes it suitable for therapy of this malignancy