Hyperprolactinemia-inducing antipsychotics increase breast cancer risk by activating JAK-STAT5 in precancerous lesions.

BACKGROUND: Psychiatric medications are widely prescribed in the USA. Many antipsychotics cause serum hyperprolactinemia as an adverse side effect; prolactin-Janus kinase 2 (JAK2)-signal transducer and activator of transcription 5 (STAT5) signaling both induces cell differentiation and suppresses apoptosis. It is controversial whether these antipsychotics increase breast cancer risk. METHODS: We investigated the impact of several antipsychotics on mammary tumorigenesis initiated by retrovirus-mediated delivery of either ErbB2 or HRas or by transgenic expression of Wnt-1. RESULTS: We found that the two hyperprolactinemia-inducing antipsychotics, risperidone and pimozide, prompted precancerous lesions to progress to cancer while aripiprazole, which did not cause hyperprolactinemia, did not. We observed that risperidone and pimozide (but not aripiprazole) caused precancerous cells to activate STAT5 and suppress apoptosis while exerting no impact on proliferation. Importantly, we demonstrated that these effects of antipsychotics on early lesions required the STAT5 gene function. Furthermore, we showed that only two-week treatment of mice with ruxolitinib, a JAK1/2 inhibitor, blocked STAT5 activation, restored apoptosis, and prevented early lesion progression. CONCLUSIONS: Hyperprolactinemia-inducing antipsychotics instigate precancerous cells to progress to cancer via JAK/STAT5 to suppress the apoptosis anticancer barrier, and these cancer-promoting effects can be prevented by prophylactic anti-JAK/STAT5 treatment. This preclinical work exposes a potential breast cancer risk from hyperprolactinemia-inducing antipsychotics in certain patients and suggests a chemoprevention regime that is relatively easy to implement compared to the standard 5-year anti-estrogenic treatment in women who have or likely have already developed precancerous lesions while also requiring hyperprolactinemia-inducing antipsychotics.

Oncogenes come of age.

Mutations of proto-oncogenes are common events in the pathogenesis of cancers, as shown in a wide range of studies during the 30 years since the discovery of these genes. The benefits of novel therapies that target the products of mutant alleles in human cancers, and the demonstrated dependence of cancers in mouse models on continued expression of initiating oncogenes, are especially promising signs that revolutionary improvements in cancer care are possible. Full realization of the promise of targeted therapies, however, will require better definitions of the genotypes of human cancers, new approaches to interrupt the biochemical consequences of oncogenic mutations, and a greater understanding of drug resistance and tumor progression. In this paper, we summarize recent efforts toward these goals in our laboratory and others.

Haploinsufficiency of the Pten tumor suppressor gene promotes prostate cancer progression.

The PTEN gene encodes a lipid phosphatase that negatively regulates the phosphatidylinositol 3-kinase pathway and is inactivated in a wide variety of malignant neoplasms. High rates of loss of heterozygosity are observed at the 10q23.3 region containing the human PTEN gene in prostate cancer and other human malignancies, but the demonstrated rate of biallelic inactivation of the PTEN gene by mutation or homozygous deletion is significantly lower than the rate of loss of heterozygosity. The transgenic adenocarcinoma of mouse prostate model is a well characterized animal model of prostate cancer. Analysis of prostate cancer progression in transgenic adenocarcinoma of mouse prostate mice bred to Pten(+/-) heterozygous mice, coupled with analysis of the Pten gene and protein in the resulting tumors, reveals that haploinsufficiency of the Pten gene promotes the progression of prostate cancer in this model system. This observation provides a potential explanation for the discordance in rates of loss of heterozygosity at 10q23 and biallelic PTEN inactivation observed in prostate cancer and many human malignancies.

An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity in Pten+/- mice.

PTEN phosphatase acts as a tumor suppressor by negatively regulating the phosphoinositide 3-kinase (PI3K) signaling pathway. It is unclear which downstream components of this pathway are necessary for oncogenic transformation. In this report we show that transformed cells of PTEN(+/-) mice have elevated levels of phosphorylated Akt and activated p70/S6 kinase associated with an increase in proliferation. Pharmacological inactivation of mTOR/RAFT/FRAP reduced neoplastic proliferation, tumor size, and p70/S6 kinase activity, but did not affect the status of Akt. These data suggest that p70/S6K and possibly other targets of mTOR contribute significantly to tumor development and that inhibition of these proteins may be therapeutic for cancer patients with deranged PI3K signaling.

Deficiency of Pten accelerates mammary oncogenesis in MMTV-Wnt-1 transgenic mice.

BACKGROUND: Germline mutations in the tumor suppressor PTEN predispose human beings to breast cancer, and genetic and epigenetic alterations of PTEN are also detected in sporadic human breast cancer. Germline Pten mutations in mice lead to the development of a variety of tumors, but mammary carcinomas are infrequently found, especially in mice under the age of six months. RESULTS: To better understand the role of PTEN in breast tumor development, we have crossed Pten heterozygous mice to MMTV-Wnt-1 transgenic mice that routinely develop ductal carcinomas in the mammary gland. Female Wnt-1 transgenics heterozygous for Pten developed mammary tumors earlier than Wnt-1 transgenics that were wild type for Pten. In most tumors arising in Pten heterozygotes, the Pten wild-type allele was lost, suggesting that cells lacking Pten function have a growth advantage over cells retaining a wild type allele. Tumors with LOH contained high levels of activated AKT/PKB, a downstream target of the PTEN/PI3K pathway. CONCLUSIONS: An animal model has been developed in which the absence of Pten collaborates with Wnt-1 to induce ductal carcinoma in the mammary gland. This animal model may be useful for testing therapies specific for tumors deregulated in the PTEN/PI3K/AKT pathway.

Mutation of Pten/Mmac1 in mice causes neoplasia in multiple organ systems.

Pten/Mmac1+/- heterozygous mice exhibited neoplasms in multiple organs including the endometrium, liver, prostate, gastrointestinal tract, thyroid, and thymus. Loss of the wild-type allele was detected in neoplasms of the thymus and liver. Surprisingly, tumors of the gastrointestinal epithelium developed in association with gut lymphoid tissue. Tumors of the endometrium, thyroid, prostate, and liver were not associated with lymphoid tissue and appeared to be highly mitotic. In addition, these mice have nonneoplastic hyperplasia of lymph nodes that was caused by an inherited defect in apoptosis detected in B cells and macrophages. Examination of peripheral lymphoid tissue including lymphoid aggregates associated with polyps revealed that the normal organization of B and T cells was disrupted in heterozygous animals. Taken together, these data suggest that PTEN is a regulator of apoptosis and proliferation that behaves as a "landscaper" tumor suppressor in the gut and a "gatekeeper" tumor suppressor in other organs.

PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer.

Mapping of homozygous deletions on human chromosome 10q23 has led to the isolation of a candidate tumor suppressor gene, PTEN, that appears to be mutated at considerable frequency in human cancers. In preliminary screens, mutations of PTEN were detected in 31% (13/42) of glioblastoma cell lines and xenografts, 100% (4/4) of prostate cancer cell lines, 6% (4/65) of breast cancer cell lines and xenografts, and 17% (3/18) of primary glioblastomas. The predicted PTEN product has a protein tyrosine phosphatase domain and extensive homology to tensin, a protein that interacts with actin filaments at focal adhesions. These homologies suggest that PTEN may suppress tumor cell growth by antagonizing protein tyrosine kinases and may regulate tumor cell invasion and metastasis through interactions at focal adhesions.

The 3'-untranslated region of CaMKII alpha is a cis-acting signal for the localization and translation of mRNA in dendrites.

Neuronal signaling requires that synaptic proteins be appropriately localized within the cell and regulated there. In mammalian neurons, polyribosomes are found not just in the cell body, but also in dendrites where they are concentrated within or beneath the dendritic spine. The alpha subunit of Ca(2+)-calmodulin-dependent protein kinase II (CaMKII alpha) is one of only five mRNAs known to be present within the dendrites, as well as in the soma of neurons. This targeted subcellular localization of the mRNA for CaMKII alpha provides a possible cell biological mechanism both for controlling the distribution of the cognate protein and for regulating independently the level of protein expression in individual dendritic spines. To characterize the cis-acting elements involved in the localization of dendritic mRNA we have produced two lines of transgenic mice in which the CaMKII alpha promoter is used to drive the expression of a lacZ transcript, which either contains or lacks the 3'-untranslated region of the CaMKII alpha gene. Although both lines of mice show expression in forebrain neurons that parallels the expression of the endogenous CaMKII alpha gene, only the lacZ transcripts bearing the 3'-untranslated region are localized to dendrites. The beta-galactosidase protein shows a variable level of expression along the dendritic shaft and within dendritic spines, which suggests that neurons can control the local biochemistry of the dendrite either through differential localization of the mRNA or variations in the translational efficiency at different sites along the dendrite.