Lifestyle Factors and Breast Cancer in Females with PTEN Hamartoma Tumor Syndrome (PHTS).

Females with PTEN Hamartoma Tumor Syndrome (PHTS) have breast cancer risks up to 76%. This study assessed associations between breast cancer and lifestyle in European female adult PHTS patients. Data were collected via patient questionnaires (July 2020-March 2023) and genetic diagnoses from medical files. Associations between lifestyle and breast cancer were calculated using logistic regression corrected for age. Index patients with breast cancer before PHTS diagnosis (breast cancer index) were excluded for ascertainment bias correction. In total, 125 patients were included who completed the questionnaire at a mean age of 44 years (SD = 13). This included 21 breast cancer indexes (17%) and 39 females who developed breast cancer at 43 years (SD = 9). Breast cancer patients performed about 1.1 times less often 0-1 times/week physical activity than ≥2 times (ORtotal-adj = 0.9 (95%CI 0.3-2.6); consumed daily about 1.2-1.8 times more often ≥1 than 0-1 glasses of alcohol (ORtotal-adj = 1.2 (95%CI 0.4-4.0); ORnon-breastcancer-index-adj = 1.8 (95%CI 0.4-6.9); were about 1.04-1.3 times more often smokers than non-smokers (ORtotal-adj = 1.04 (95%CI 0.4-2.8); ORnon-breastcancer-index-adj = 1.3 (95%CI 0.4-4.2)); and overweight or obesity (72%) was about 1.02-1.3 times less common (ORtotal-adj = 0.98 (95%CI 0.4-2.6); ORnon-breastcancer-index-adj = 0.8 (95%CI 0.3-2.7)). Similar associations between lifestyle and breast cancer are suggested for PHTS and the general population. Despite not being statistically significant, results are clinically relevant and suggest that awareness of the effects of lifestyle on patients' breast cancer risk is important.

"It was an important part of my treatment": a qualitative study of Norwegian breast Cancer patients' experiences with mainstreamed genetic testing.

BACKGROUND: In South-Eastern Norway, genetic testing for BRCA1 and BRCA2 is offered to breast cancer patients by their treating surgeon or oncologist. Genetic counselling from a geneticist or a genetic counsellor is offered only to those who test positive for a pathogenic variant or have a family history of cancer. This practice is termed "mainstreamed genetic testing". The aim of this study was to learn about patients' experience of this healthcare service. METHODS: Qualitative in-depth interviews were conducted with 22 breast cancer patients who had been diagnosed during the first half of 2016 or 2017 at one regional and one university hospital and who had been offered testing by their treating physician. A six-phase thematic approach was used to analyse the data. RESULTS: The participants had varied experiences of how and when testing was offered. Three main themes emerged from the analysis: 1. informational and communicational needs and challenges during a chaotic time, 2. the value of genetic testing and 3. the importance of standardised routines for mainstreamed genetic testing. CONCLUSIONS: Despite the shock of their diagnosis and the varying experiences they had in respect of how and when testing was offered, all of the participants emphasised that genetic testing had been an important part of their diagnosis and treatment. Our results indicate that there is a need for continuous collaboration between geneticists, surgeons, oncologists and laboratory specialists in order to establish simple and robust routines so as to ensure that all eligible breast cancer patients are offered testing at a point when the test result can have an impact on treatment.

Birt-Hogg-Dubé syndrome. / Birt-Hogg-Dubé-syndrom.

Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant genetic disorder characterised by pulmonary cysts, fibrofolliculomas and renal tumours. The pulmonary cysts may lead to pneumothorax, and in cases of primary, spontaneous pneumothorax the syndrome should be excluded. The renal tumours are frequently malignant, but slow-growing. Screening and family assessment enable discovery of renal cancer at an early stage. The syndrome is underdiagnosed and little known.

Mainstreamed genetic testing of breast cancer patients in two hospitals in South Eastern Norway.

Studies have shown that a significant number of eligible breast cancer patients are not offered genetic testing or referral to genetic counseling. To increase access to genetic testing in South Eastern Norway, testing has since 2014 been offered directly to breast cancer patients by surgeons and oncologists. This practice is termed "mainstreamed genetic testing". The aim of this study was to investigate to what extent patients in South Eastern Norway are offered testing. Three hundred and sixty one patients diagnosed in 2016 and 2017 at one regional and one university hospital in South Eastern Norway were included. Data on whether the patients fulfilled the criteria, whether they had been offered testing and if they were tested were collected. In total, 26.6% (96/361) fulfilled the criteria for testing. Seventy five percent (69/92) of these were offered testing, and 71.7% (66/92) were tested. At the university hospital, 90.2% (37/41) of eligible patients were offered testing, and at the regional hospital 62.7% (32/51). Fifty two percent (12/23) of eligible patient not offered testing were younger than 50 years at time of diagnosis. As many as 95.4% (125/131) of all patients who were offered testing, wanted to be tested. The majority of patients who fulfilled the criteria were offered testing, supporting the practice of mainstreamed genetic testing. There were nevertheless differences in rates of testing between the hospitals that affected all groups of patients, indicating that genetic testing may not be equally accessible to all patients. We suggest that efforts should be made to increase awareness and improve routines for genetic testing of breast cancer patients in Norway.

The fatty acid binding protein 7 (FABP7) is involved in proliferation and invasion of melanoma cells.

BACKGROUND: The molecular mechanisms underlying melanoma tumor development and progression are still not completely understood. One of the new candidates that emerged from a recent gene expression profiling study is fatty acid-binding protein 7 (FABP7), involved in lipid metabolism, gene regulation, cell growth and differentiation. METHODS: We studied the functional role of FABP7 in human melanoma cell lines and using immunohistochemistry analyzed its expression pattern and clinical role in 11 nevi, 149 primary melanomas and 68 metastases. RESULTS: FABP7 mRNA and protein level is down-regulated following treatment of melanoma cell lines with a PKC activator (PMA) or MEK1 inhibitor (PD98059). Down-regulation of FABP7 using siRNA decreased cell proliferation and invasion but did not affect apoptosis. In clinical specimens, FABP7 was expressed in 91% of nevi, 71% of primary melanomas and 70% of metastases, with a cytoplasmic and/or nuclear localization. FABP7 expression was associated with tumor thickness in superficial spreading melanoma (P = 0.021). In addition, we observed a trend for an association between FABP7 expression and Ki-67 score (P = 0.070) and shorter relapse-free survival (P = 0.069) in this group of patients. CONCLUSION: Our data suggest that FABP7 can be regulated by PKC and the MAPK/ERK1/2 pathway through independent mechanisms in melanoma cell lines. Furthermore, FABP7 is involved in cell proliferation and invasion in vitro, and may be associated with tumor progression in melanoma.

Activation of c-jun N-terminal kinase is associated with cell proliferation and shorter relapse-free period in superficial spreading malignant melanoma.

Signaling pathways regulating cell proliferation and survival have become attractive targets for anticancer strategies. In the present study, we analyzed by immunohistochemistry, a panel of benign nevi, superficial spreading and nodular primary melanomas and metastases for expression of activated p38/mitogen-activated protein kinase (p-p38) and c-jun N-terminal kinase (JNK) (p-JNK) and correlated the findings with known prognostic variables. Twenty-five and 35% of the primaries and 9 and 25% of the metastases expressed variable levels of p-p38 and p-JNK, respectively. In benign nevi, 73.5% expressed p-JNK and 7% expressed p-p38. For patients with superficial spreading melanomas, high level of cytoplasmic p-JNK was associated with thicker tumors (P=0.017) and shorter disease-free survival (P=0.003) as well as with markers of cell proliferation (cyclin A (P=0.017) and p21 (P=0.021)). In nodular melanomas, nuclear p-p38 was associated with Ki-67 (P=0.012), but neither cytoplasmic nor nuclear localized p-p38 was associated with disease outcome. Of note, in superficial spreading melanomas, a positive correlation between cytoplasmic p-JNK and cytoplasmic p-extracellular signal-regulated kinase ERK(1/2) (P=0.005) and p-p38 (P=0.003) was observed. Likewise, p-p38 in cytoplasm was positively associated with cytoplasmic p-ERK1/2 (P<0.0005) and p-Akt (P=0.047). In contrast, except for a positive correlation between nuclear p-p38 and membranous p-TrkA (P=0.02), no correlation between the activation status of the different signaling pathways was observed in nodular melanomas. In conclusion, our results suggest that in benign nevi activated JNK may have a role in restricting uncontrolled cell proliferation or survival. However, during tumor progression, activation of JNK is associated with cell proliferation and shorter relapse-free period for patients with superficial spreading melanomas, suggesting that the JNK activation status could be a marker for clinical outcome in at least a subgroup of malignant melanoma. In contrast, activation of p38 seems to play a less important role in development and progression of malignant melanomas.

Phorbol ester phorbol-12-myristate-13-acetate promotes anchorage-independent growth and survival of melanomas through MEK-independent activation of ERK1/2.

The phorbol ester, phorbol-12-myristate-13-acetate (PMA), an activator of PKCs, is known to stimulate the in vitro growth of monolayer cultures of normal human melanocytes whereas it inhibits the growth of most malignant melanoma cell lines. We examined the effect of PMA on proliferation and survival of melanoma cells grown as multicellular aggregates in suspension (spheroids), and aimed to elucidate downstream targets of PKC signaling. In contrast to monolayer cultures, PMA increased cell proliferation as well as protected melanoma cells from suspension-mediated apoptosis (anoikis). Supporting the importance of PKC in anchorage-independent growth, treatment of anoikis-resistant melanoma cell lines with antisense oligonucleotides against PKC-alpha, or the PKC inhibitor Gö6976, strongly induced anoikis. PMA induced activation of ERK1/2, but this effect was not prevented by the MEK inhibitors PD98059 or by U0126. Whereas PD98059 treatment alone led to marked activation of the pro-apoptotic Bim and Bad proteins and significantly increased anoikis, these effects were clearly reversed by PMA. In conclusion, our results indicate that the protective effect of PMA on anchorage-independent survival of melanoma cells at least partly is mediated by MEK-independent activation of ERK1/2 and inactivation of downstream pro-apoptotic effector proteins.

Deacetylase inhibition in malignant melanomas: impact on cell cycle regulation and survival.

In the present study the deacetylase inhibitor trichostatin A (TSA) was used to elucidate the effect of protein acetylation on cell cycle progression and survival in seven human malignant melanoma cell lines. It was shown that TSA treatment led to a transient G(2)/M phase delay and accumulation of unphosphorylated retinoblastoma protein (pRB) in all cases. TSA significantly induced protein expression of the cyclin-dependent kinase inhibitor p21(WAF1/CIP1) in a dose-dependent manner in all cell lines including those not expressing p21(WAF1/CIP1) constitutively, whereas the levels of both wild-type and mutated p53 protein were reduced. The effect on p53 was not a direct result of inhibition of extracellular signal-regulated kinase-1/2 (ERK1/2) activation by TSA, as treatment of the cells with the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase-1 (MEK1) inhibitor PD98059 did not result in decreased p53 protein level. Furthermore, TSA treatment led to reduction in cyclin D1 whereas cyclin D3 accumulated, the latter due to increased protein stability. Similarly, cyclin A protein was reduced whereas cyclin E level was elevated. The effect on p27(Kip1), CDK4 and CDK2 was only marginal. In all the examined cell lines, TSA treatment resulted in a profound induction of apoptosis and cleavage of poly-(ADP-ribose)-polymerase (PARP) indicative of caspase activity. Similarly, TSA-mediated apoptosis was reversed by the caspase-inhibitor z-vad-fmk. Altogether, these results suggest that p21(WAF1/CIP1) in melanomas is silenced by deacetylation, and furthermore that inhibition of deacetylation may have potential in anticancer therapy of melanoma patients.

Expression of activated extracellular signal-regulated kinases 1/2 in malignant melanomas: relationship with clinical outcome.

PURPOSE: The purpose of the present work was to analyze the protein expression of activated extracellular signal-regulated kinases 1 and 2 (ERK1/2) in a panel of superficial spreading (SSM) and nodular (NM) primary and metastatic melanomas, and to correlate the expression level with clinicopathological parameters. EXPERIMENTAL DESIGN: Expression of activated ERK1/2 was examined by immunohistochemistry in 172 primary melanomas (108 SSM and 64 NMs), 67 metastatic lesions, and in 41 benign nevi. RESULTS: Fifty four percent of primary and 33% of metastatic melanomas expressed variable levels of activated ERK1/2. No immunoreactivity was detected in benign nevi. In 21% of the primaries only cytoplasmic expression was detected, whereas 3% and 30% showed positive immunoreactivity in either nucleus or cytoplasm and nucleus, respectively. Activated ERK1/2 expression varied significantly with the thickness of superficial spreading melanomas, with lower expression in thinner lesions (P = 0.016). A significant correlation between activated ERK1/2 and cyclin D1 (P = 0.031) in nodular, as well as between activated ERK1/2 and cyclin D3 (P = 0.030) in SSMs were observed. The protein level of p27(Kip1) correlated with activated ERK1/2 (P = 0.048) in the nucleus. Furthermore, a strong inverse correlation between activated ERK1/2 and membrane-bound beta-catenin (P = 0.004) in nodular melanomas was revealed. Activation of ERK1/2 did not have any impact on relapse-free or overall survival. CONCLUSION: Our results suggest that activation of ERK1/2 may be involved in cell cycle regulation in SSMs. Moreover, the inverse association between membrane-bound beta-catenin and ERK1/2 in NMs suggest that ERK1/2 activation may play a role in decreasing homotypic interactions through destabilization of beta-catenin.

Expression of estrogen receptors alpha and beta in human lung tissue and cell lines.

Epidemiological studies have indicated that females may be at greater risk of smoking associated lung cancer compared with males. Several lines of biochemical evidence support these observations. A possible role of circulating steroid hormones in the etiology of lung cancer has been hypothesized. In the present paper, we have studied the expression of the estrogen receptors (ER)-alpha and ER beta in histologically normal human lung tissue and lung tumor cell lines. Relative ER mRNA levels were measured by reverse transcriptase-PCR and normalized to the level of expression of the glyceraldehyde 3-phosphate dehydrogenase gene (GAPDH). In lung tissue, an ER alpha transcript was found at various levels in 38 out of 46 cases (83%). ER beta was expressed in all cases. The ERs were expressed at similar levels in females and males, and the levels of ER alpha and ER beta mRNA were significantly related (P<0.0001). Compared with the lung tissue, ER expression levels were lower in 16 human lung tumor cell lines and two immortalized human bronchial epithelial cell lines. Five of the tumor cell lines (31%) expressed detectable levels of ER alpha and both of the immortalized cell lines showed a weak ER alpha expression level. All cell lines expressed the ER beta. The lung cell lines BEAS-2B and DB354 showed significantly reduced cell proliferation in response to tamoxifen and a minor increased growth in response to 17 beta-estradiol. In conclusion, ER genes are abundantly expressed in both histologically normal human lung and lung tumor cell lines. This indicates a possible role of ERs in lung carcinogenesis.