Critical role played by thyroid hormone in induction of neoplastic transformation by chemical carcinogens in tissue culture.

Abstract

Incubation of primary cultures of hamster embryo cells (HEC) or mouse fibroblasts (C3H/IOTI/2 cells) in media depleted of thyroid hormones does not alter cell growth or survival but renders the cells resistant to neoplastic transformation by benzo [a]pyrene (B[a]P) or N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), carcinogens which yield transformation rates of 10-4_10-2 in media supplemented with triiodothyronine (T3). In C3H/10T'/2 cells, the times of addition or removal of the hormone indicate that T3 exerts maximum effect when added 12 hr prior to treatment with B[a]P and that the progression of transformation from the time of initiation by the carcinogen to full expression and the appearance of transformed foci was independent of the presence or absence of the hormone in the medium. Dependence of transformation on T3 concentration in the medium was observed over the physiological range of 1 pM to 100 nM in C3H/1OT1/2 cells treated with B[a]P. These results were similar to our previous findings on the T3 dose-related induction of radiogenic transformation and of Na+,K+-ATPase activity. The latter effect was used as a measure of T3 induction of protein synthesis. A further indication of the potential involvement of protein synthesis in T3 action is the suppression of T3-and B[a]P-dependent transformation by cycloheximide at concentrations that inhibit protein synthesis by ==50% in the C3H/1OT'12 cells. We suggest that thyroid hormone induces the synthesis of a host protein that plays a key role in neoplastic transformation by direct-acting chemical carcinogens and by those requiring metabolic activation. In our previous studies, similar T3-dependent mechanisms were implicated in radiogenic transformations.Our earlier studies, with primary cultures of hamster embryo cells (HEC) and mouse embryo fibroblasts (C3H/LOTI/2), an established line, indicated that thyroid hormones are essential factors in the induction of neoplastic transformation by x-irradiation (1, 2). Removal of triiodothyronine (T3) and thyroxine (T4) from serum-supplemented media eliminated radiogenic transformation in both cellular systems without modifying the rates of cell survival or cell growth (1, 2). The addition of T3 (1 pM to 100 nM) to the thyroid hormone-depleted medium reestablished transformation at frequencies that were T3 dose dependent. The T3 concentration dependence of the transformation response to x-rays was the same as the concentration dependence of the Na+,K+-ATPase response (2).In these earlier studies (2), the maximal transformation frequency was observed when T3 was added to the medium 12 hr prior to x-ray treatment. In contrast, when T3 was added to the hormone-depleted cells 24-48 hr after exposure to x-rays, no transformation was observed. These findings strongly suggested that thyroid hormones serve as crucial factors in the initiation of cellular neoplastic transformation by x-irradiation.The present experiments were undertaken to assess the role of thyroid hormone in neoplastic transformation induced by spec...

Expression of the ErbA-beta class of thyroid hormone receptors is selectively lost in human colon carcinoma.

“…Thus, erbA gene products probably mediate thyroid hormone induction of tissuespecific genes necessary for differentiation of organs such as brain, heart, pituitary and liver (14)(15)(16)(17). Finally, erbA products may mediate the documented activity ofthyroid hormone as a potentiator of carcinogens in some systems (18,19).…”

Tumorigenic methylcholanthrene transformants of C3H/10T1/2 cells have a common nucleotide alteration in the c-Ki-ras gene.

“…Both of these processes can be manipulated for the c-Ki-ras gene in the C3H/10TY2 cell culture transformation system. Borek et al (21) have shown that thyroid hormone is an important "cofactor" for chemical transformation of C3H/1OTY2 cells. Guernsey and Leuthauser (22) showed that the presence of triiodothyronine in the medium immediately prior to and during exposure to MCA increased the transformation frequency of C3H/1OTY2 cells by as much as 6- 24).…”

Newly-Recognized Small Molecule Receptors on Human Breast Cancer Cell Integrin αvβ3 that Affect Tumor Cell Behavior

“…That estrogen may support breast tumor growth nongenomically is now under consideration (Silva & Shupnik, 2007), perhaps involving nuclear ERα insinuated into the plasma membrane or ER-like proteins in the membrane (Levin, 2011). The concept that thyroid hormone may be a growth factor for breast cancer has been advanced by various investigators (Goodman et al, 1980;Borek et al, 1983;Cristofanilli et al, 2005). That thyroid hormone could nongenomically support ER-positive human breast cancer cell proliferation and to be estrogen-like was shown when T 4 caused MAPKdependent specific serine phosphorylation of nuclear ER, mimicking estradiol upon which depended stimulation of proliferation by the iodothyronine.…”